CA3225894A1 - Aak1 inhibitor and use thereof - Google Patents

Abstract

A compound of formula (I) and a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition containing same, and the use thereof as an AAK1 inhibitor in the preparation of a drug for treating related diseases.

Description

Technical Field The present invention belongs to the field of drugs, and in particular relates to 5 a derivative of a protein arginine methyltransferase inhibitor, or a stereoisomer, pharmaceutically acceptable salt, solvate, co-crystal or deuterated compound thereof, and the use thereof in the preparation of a drug for treating related diseases mediated by AAK1.
10 Background Art Adaptor-associated kinase 1 (AAK1) is a member of the Arkl/Prkl family of serine/threonine kinases. AAK1 mRNA exists in two splice forms known as the short form and the long form. The long form is predominant and is highly expressed in the brain and heart (Henderson and Conner, Mol. Biol. Cell. 2007, 18, 15 2698-2706). AAK1 is enriched in the synaptosomal preparation and is co-localized with endocytic structures in cultured cells. AAK1 regulates the endocytosis involving clathrin coats, a key process in synaptic vesicle recycling and receptor-mediated endocytosis. AAK1 binds to an AP2 complex, which is a heterotetramer connecting the receptor cargo with the clathrin coat. Clathrin-AAK1 binding 20 stimulates AAK1 activity (Conner et al., Traffic 2003, 4, 885-890;
Jackson et al., J.
Cell. Biol. 2003, 163, 231-236). AAK1 phosphorylates the mu-2 subunit of AP-2, which enhances the binding of mu-2 to tyrosine-containing sorting motifs on the cargo receptor (Ricotta et al., J. Cell Bio. 2002, 156, 791-795; Conner and Schmid, J. Cell Bio. 2002, 156, 921-929). Phosphorylation of Mu2 is not required by 25 receptor uptake, but improves the internalization efficiency (Mutely et al., Mol.
Biol. Cell. 2006, 17,5298-5308).
AAK1 has been identified as an inhibitor of Neuregulin-1/ErbB4 signalling in PC12 cells. Loss of AAK1 expression via RNA interference-mediated gene silencing or by treatment with the kinase inhibitor K252a (which inhibits AAK1 30 activity) potentiates Nrg 1-induced neurite outgrowth. Such treatments result in increased ErbB4 expression and increased ErbB4 accumulation in the plasma membrane or in close proximity to the plasma membrane (Kuai et al., Chemistry and Biology 2011, 18, 891-906). NRG1 and ErbB4 are putative susceptibility genes of schizophrenia (Buonanno, Brain Res. Bull. 2010, 83, 122-131). The SNPs

- 2 -in both genes are associated with multiple endophenotypes of schizophrenia (Greenwood et al., Am. J. Psychiatry 2011, 168, 930-946). Mouse models for NRG1 and ErbB4K0 have displayed morphological changes and behavioural manifestations related to schizophrenia (Jaaro-Peled et al., Schizophrenia Bulletin 5 2010, 36, 301-313; Wen et al., Proc. Natl. Acad. Sci. USA. 2010, 107, 1211-1216).
Furthermore, the single nucleotide polymorphism in the introns of the AAK1 gene has been implicated with the onset age in Parkinson's disease (Latourelle et al., BMC Med. Genet. 2009, 10, 98). These results show that the inhibition of AAK1 activity is useful in treating schizophrenia, cognitive deficit in schizophrenia, 10 Parkinson's disease, neuropathic pain, bipolar disorder and Alzheimer's disease.
Summary of the Invention The compound and the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof provided in the 15 present invention have an inhibitory effect on AAK1, can inhibit cell proliferation, possess good pharmacokinetic characteristics, high bioavailability, good safety, high selectivity and low toxicity and side effects, can be administered orally, and have fast absorption, high clearance rate and other advantages. Moreover, it has surprisingly been found that the compound of the present invention has a good 20 brain penetrability.
The present invention relates to a compound of formula (I). (Ia), (lb) or (II), or a stereoisomer, deuterated compound, solvate. prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, x.;x3 N
,R2 Y

Y2 , R62 2 Yi R41 R42 R4'1 R42 25 (1) (Ia) N N' N. ,CHF2 N, R2 R
,R62 - 2' -'<R63 'Cr' X

(II) (Ib) wherein

- 3 -Xi, X2, X3 and X4 are each independently selected from N or CRx; in certain embodiments, X1 is selected from N, and X2, X3 and X4 are each independently selected from N or CRx; in certain embodiments, Xi is selected from N, and X2, and X4 are each independently selected from CRx;
5 Yi, Y7 and Y3 are each independently selected from N or CRY; in certain embodiments, Yi is selected from N, and Y2 and Y3 are each independently selected from N or CRY; in certain embodiments, Yi is selected from N, and Y,"
and Y3 are each independently selected from CRY;
Z is selected from NR' or 0; in certain embodiments, Z is selected from 0; in 10 certain embodiments, Z is selected from NR';
R' is selected from H, deuterium, halogen, C1-6 alkyl, halo C1_6 alkyl, or deuterated CI-6 alkyl; in certain embodiments, R7 is selected from H, deuterium, halogen, C1_4 alkyl, halo C1_4 alkyl, or deuterated C1_4 alkyl; in certain embodiments, 12' is selected from H, deuterium, F, Cl, C1_2 alkyl, halo C1_2 alkyl, or 15 deuterated C1_2 alkyl; in certain embodiments, R' is selected from H, deuterium, F, Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F. -CH2CHF2, -CH2CF3, -CHFCH2F, -CTFCHF2, -CIFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CIDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, or -CD2CD3;
20 Rx and RY are each independently selected from H, deuterium, halogen, amino, nitro, cyano, hydroxyl, sulphonyl, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, C1_6 alkoxy, halo C1_6 alkoxy, deuterated C1_6 alkoxy, hydroxy C1-6 alkyl, C3-6 cycloalkyl, or C4_6 heterocycloalkyl; in certain embodiments, Rx and RY are each independently selected from H, deuterium, halogen, amino, nitro, cyano, hydroxyl, 25 sulphonyl, CI-4 alkyl, halo C1-4 alkyl, deuterated C1_4 alkyl. C1_4 alkoxy, halo C1-4 alkoxy, deuterated C1_4 alkoxy, hydroxy C1_4 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl. or 6-membered heterocycloalkyl; in certain embodiments, Rx and RY are each independently 30 selected from H, deuterium, F, Cl, amino, nitro, cyano, hydroxyl, sulphonyl, alkyl, halo C1_2 alkyl, deuterated C1_2 alkyl, C1_2 alkoxy, halo C1_2 alkoxy, deuterated C1_2 alkoxy, hydroxy C1_2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl;

- 4 -unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0, and the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA;
RI and R2 are each independently selected from H, deuterium, halogen,

5 amino, -COON, cyano, sulphonyl, aminoacyl, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, deuterated C1-6 alkoxy, hydroxy C1-6 alkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, -NIC(0)C1-6 alkyl, -NI-IC(0)C3-6 cycloalkyl, -NHC(0)C4_6 heterocycloalkyl, -NHC(0)NHCi_6 alkyl, or -10 NHC(0)0C1_6 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents; in certain embodiments, RI
and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulphonyl, aminoacyl, C1_4 alkyl, halo C1_4 alkyl, deuterated C1_4 alkyl, C1-4 alkoxy, halo C1_4 alkoxy, deuterated C1_4 alkoxy, hydroxy C1-4 alkyl, 3-membered 15 cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(0)C1 _4 alkyl, -NI-IC(0)C36 cycloalkyl, -NHC(0)C4_6 heterocycloalkyl, -NIC(0)NHC 1_4 alkyl, or -NHC(0)0C1_4 alkyl; in certain embodiments, RI and R2 are each independently selected from H, 20 deuterium, F, Cl, amino, -COOK cyano, sulphonyl, aminoacyl, C1_2 alkyl, halo C1-2 alkyl, deuterated C1-2 alkyl, C1-2 alkoxy, halo C1_2 alkoxy, deuterated C1-2 alkoxy, hydroxy C1_2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl. 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(0)C1_ 2 alkyl, -NHC(0)C3-4 25 cycloalkyl, -NHC(0)C4_5 heterocycloalkyl, -NHC(0)NHCI -2 alkyl, or -NHC(0)0C1_2 alkyl; in certain embodiments, RI and R2 are each independently selected from H, deuterium, cyano, halo C1_2 alkyl, halo C1_2 alkoxy, -NHC(0)C1-2 alkyl, -NHC(0)0C1_2 alkyl, or -NHC(0)C3_4 cycloalkyl; in certain embodiments, RI and R2 are each independently selected from cyano, halo C1_2 alkyl, -30 NHC(0)C1_2 alkyl, -NHC(0)0C1_2 alkyl, or -NHC(0)C3_4 cycloalkyl; in certain embodiments, RI and R2 are each independently selected from cyano, -Cl-12F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, f\l"
-CF2CH2F, -CF2CHF2, -CF2CF3, -NHC(0)CH3, -NHC(0)0CH3, F, ____________________ `4 N / H
H , or F F
; in certain embodiments, RI and R2 are each independently selected from H, deuterium, halogen, amino, -COOH, cyano, sulphonyl, C16 alkyl, halo C16 alkyl, deuterated C16 alkyl. C16 alkoxy, halo alkoxy, deuterated C1-6 alkoxy, hydroxy C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocycloalkyl, -NHC(0)C1_6 alkyl, or -NHC(0)0C1_6 alkyl; in certain embodiments, RI and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulphonyl, C1_4 alkyl, halo C1_4 alkyl, deuterated C1_4 alkyl, C14 alkoxy, halo C1_4 alkoxy, deuterated C1_4 alkoxy, hydroxy C1_4 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(0)C1 -4 alkyl, or -NHC(0)0C1 4 alkyl; in certain embodiments, RI and R2 are each independently selected from H. deuterium, F, Cl, amino, -COOH, cyano, sulphonyl, C1-2 alkyl, halo C1_2 alkyl, deuterated C1_2 alkyl, C1_2 alkoxy, halo C1_2 alkoxy, deuterated alkoxy, hydroxy C1-2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(0)C1 -2 alkyl, or -NI-IC(0)0C12 alkyl; in certain embodiments, RI and R2 are each independently selected from 14, deuterium, halo C1_2 alkyl, or halo C1_2 alkoxy; in certain embodiments, RI and R2 are each independently selected from halo C1_2 alkyl;
in certain embodiments, RI and R2 are each independently selected from -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, or -CF2CF3; unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0, and the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA; in certain embodiments, RI is selected from sulphonyl, aminoacyl, halo C1_3 alkyl, -NHC(0)C1 _4 alkyl, -NHC(0)C3 -6 cycloalkyl, -NHC(0)C4_6 heterocycloalkyl, -NHC(0)NHC1_4 alkyl, or -NHC(0)0C1_4 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents;
R2 is selected from cyano, CI -3 alkyl, halo C1-3 alkyl, or deuterated CI -3 alkyl;
R3I and R32 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, CI _6 alkyl, halo C1_6 alkyl, deuterated CI-6 alkyl, CI -6 alkoxy, halo

- 6 -C1-6 alkoxy, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; or R31 and R32 together with the carbon atom to which they are attached form C3-6 cycloalkyl or 4- to membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents; in certain embodiments, R3' 5 and R32 are each independently selected from H. deuterium, F, Cl, cyano, hydroxyl, C1_4 alkyl, halo C1_4 alkyl, deuterated C1_4 alkyl, C1_4 alkoxy, halo C1-4 alkoxy, deuterated CI _4 alkoxy, or hydroxy Ci_4 alkyl, or R31 and R32 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl. or 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA substituents; in certain embodiments, R31 and R32 are each independently selected from H, deuterium, F. Cl, hydroxyl, C1_2 alkyl, halo C1_2 alkyl, deuterated C1_2 alkyl, C1_2 alkoxy, halo C1_2 alkoxy, deuterated C1-2 15 alkoxy, or hydroxy C1_2 alkyl, or R31 and R32 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, or 4-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA substituents; unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S
and 0;
20 R41 and R42 are each independently selected from H, deuterium, amino, C

alkyl, halogen, cyano, hydroxyl, halo C1-6 alkyl, deuterated C1-6 alkyl, C16 alkoxy, halo C1-6 alkoxy, -C1_6 alkyl-C3_6 cycloalkyl, C3-6 cycloalkyl, C4_6 heterocycloalkyl, deuterated C1_6 alkoxy, or hydroxy C1_6 alkyl; in certain embodiments, R41 and are each independently selected from H, deuterium, amino, C1_4 alkyl, halogen, 25 cyano, hydroxyl, halo C14 alkyl, deuterated C1_6 alkyl, C1_4 alkoxy, halo C1-4 alkoxy, -C1_4 alkyl-3-membered cycloalkyl, -C1_4 alkyl-4-membered cycloalkyl, -C14 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 30 deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl;
in certain embodiments, R41 is selected from H, deuterium, amino, C1_4 alkyl, halogen, cyano, hydroxyl, halo C1_4 alkyl, deuterated Co alkyl, C14 alkoxy, halo CI _4 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -CI _4 alkyl-4-membered cycloalkyl, -C14 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-

- 7 -membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1_4 alkoxy, or hydroxy C1-4 alkyl; in certain embodiments, R41 is selected from H, deuterium, amino, C14 alkyl, halogen, 5 cyano, hydroxyl, halo C1-2 alkyl, deuterated C1_2 alkyl, C1_2 alkoxy, halo C1_2 alkoxy, -C1_2 alkyl-3-membered cycloalkyl, -C1-2 alkyl-4-membered cycloalkyl, -CI _2 al kyl -5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 10 deuterated C1_2 alkoxy, or hydroxy C1_2 alkyl:
in certain embodiments, R42 is selected from H, hydroxyl, amino, C1-2 alkyl, deuterated C1-2 alkyl, or C1-2 alkoxy; in certain embodiments, R42 is selected from amino; unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0;
15 or R41 and R42 together foma C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl containing 1 heteroatom selected from 0 or S, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA

substituents; in certain embodiments, R41 and R42 together form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered 20 cycloalkyl, or 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl containing 1 heteroatom selected from 0 or S, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 substituents;
R51 and R52 are each independently selected from H, deuterium, amino, 25 halogen, C1-6 alkyl, cyano, hydroxyl, halo C1_6 alkyl, deuterated C1_6 alkyl, C1-6 alkoxy, halo C1_6 alkoxy, -C1_6 alkyl-C1_6 cycloalkyl, C3_6 cycloalkyl, C4-6 heterocycloalkyl, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; or R51 and together with the carbon atom to which they are attached form C3-6 cycloalkyl or 4-to 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are 30 optionally further substituted with 1-3 RA substituents; in certain embodiments, R51 and R52 are each independently selected from H, deuterium, amino, F, Cl, C1-4 alkyl, cyano, hydroxyl, halo C1_4 alkyl, deuterated C1_4 alkyl, C1_4 alkoxy, halo C1-4 alkoxy, -C1_4 alkyl-3-membered cycloalkyl, -C1_4 alkyl-4-membered cycloalkyl, -C1-4 al kyl-5-m embered cycloalkyl, 3-membered cycloalkyl, 4-membered

- 8 -cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1-4 alkyl; or R51 and R52 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl, wherein the cycloalkyl and h et erocycl oal kyl are optionally further substituted with 1, 2 or 3 RA substituents; in certain embodiments, R51 and R52 are each independently selected from H, deuterium, amino, F, Cl, C1-4 alkyl, cyano, hydroxyl, halo C12 alkyl, deuterated C1_2 alkyl, C1_2 alkoxy, halo C1_2 alkoxy, -Ci -2 alkyl -3-membered cycloalkyl, -C1_2 alkyl-4-membered cycloalkyl, -C1_2 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl. 6-membered heterocycloalkyl, deuterated C12 alkoxy, or hydroxy C1_2 alkyl, or R51 and R52 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 4-membered heterocycloalkyl, or 5-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA
substituents; in certain embodiments, R51 and R52 are each independently selected from H, deuterium, amino, F, Cl, C1_4 alkyl, cyano, hydroxyl, halo C1_2 alkyl, or R51 and R52 together with the carbon atom to which they are attached form 3-membered cycloalkyl; unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0;
R61, R62 and K are each independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C1_6 alkyl, halo C1-6 alkyl, deuterated C1_6 alkyl, C1-alkoxy, halo C1_6 alkoxy, -C1_6 alkyl-C1_6 cycloalkyl, C1_6 cycloalkyl, C4-6 heterocycloalkyl, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; in certain embodiments, R61, R62 and R63 are each independently selected from H, deuterium, F, Cl, amino, cyano, hydroxyl, C1_4 alkyl, halo C1_4 alkyl, deuterated C1_4 alkyl, C1-4 alkoxy, halo C1_4 alkoxy, -C1_4 al ky1-3-m emb ered cycloalkyl, -C1_4 alkyl-4-membered cycloalkyl, -C1_4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1_4 alkyl; in certain

- 9 -embodiments, R61, R62 and R63 are each independently selected from H, deuterium, F, Cl, amino, cyano, hydroxyl, C1_2 alkyl, halo C1_2 alkyl, deuterated C1_2 alkyl, C1-2 alkoxy, halo C1-2 alkoxy, -C1-2 alkyl-3-membered cycloalkyl, -C1_2 alkyl-4-membered cycloalkyl, -C12 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 5 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C _2 alkoxy, or hydroxy Ci2 alkyl; in certain embodiments, R61, R62 and R63 are each independently selected from H, deuterium, F, Cl. amino, cyano, hydroxyl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CI-12D, -CTD2, -CD3, -CH2CH2D, -CH2C1-ID2, -CI-12CD3, -CIDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3, methoxy, ethoxy, -OCHF2, -OCH2F, -0CF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCHFCH2F, -OCHFCHF2, -OCHFCF3, -0CF2CH2F, -0CF2CHF2, -0CF2CF3, -methyl-3-membered cycloalkyl, -ethyl-3-membered cycloalkyl, -methy1-4-membered cycloalkyl, -ethyl-4-membered cycloalkyl, -methyl-5-membered cycloalkyl, -ethyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -OCHD2, -OCH2D, -OCD3, -OCH2CH2D, -OCH2C14D2, -OCH2CD3, -OCHDCH2D, -OCHDCHD2, -OCHDCD3, -0CD2CH2D, -0CD2CHD2. -0CD2CD3, -CH2OH, or -CH2CH2OH;
unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0;
or, R31 and R41, or R41 and R51 together with the carbon atoms to which they 25 are each attached form C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents; in certain embodiments, R31 and R41, or R41 and R51 together with the carbon atoms to which they are each attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered 30 cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA substituents; unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S
and 0;

or, R4I and R61, or R' and R41 together with the atoms to which they are each attached form C4-6 cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA

substituents; in certain embodiments, R41 and R61, or R' and R41 together with the 5 atoms to which they are each attached form 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA
substituents;
unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected

10 from N, S and 0;
or, R5I and R61, or R61 and R62 together with the carbon atom(s) to which they are each attached form C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or a double bond, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents; in certain embodiments, R51 and R61, or 15 and R62 together with the carbon atom(s) to which they are each attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, or a double bond, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA
20 substituents; unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0;
or, R61, R62 and R63 together with the carbon atom to which they are attached form Cs_io bridged ring, or Csii spiro ring, wherein the bridged ring and spiro ring are optionally further substituted with 1-3 RA substituents; in certain embodiments, 25 R61, R62 and K-63 together with the carbon atom to which they are attached form 5-membered bridged ring. 6-membered bridged ring, 7-membered bridged ring, 8-membered bridged ring, 5-membered spiro ring, 6-membered spiro ring, 7-membered spiro ring, 8-membered spiro ring, 9-membered spiro ring, 10-membered spiro ring, or 1 1-membered spiro ring, wherein the bridged ring and 30 spiro ring are optionally further substituted with 1, 2 or 3 RA
substituents; in certain embodiments, R61, R62 and R63 together with the carbon atom to which they are attached form 5-membered saturated carbocyclic bridged ring, 6-membered saturated carbocyclic bridged ring, 7-membered saturated carbocyclic bridged ring, 8-membered saturated carbocyclic bridged ring, 3-membered carbocycle-spiro-3-

- 11 -membered carbocyclyl, 3-membered carbocycle-spiro-4-membered carbocyclyl, 3-membered carbocycle-spiro-5-membered carbocyclyl, 3-membered carbocycle-spiro-6-membered carbocyclyl, 4-membered carbocycle-spiro-3-membered carbocyclyl, 4-membered carbocycle-spiro-4-membered carbocyclyl. 4-membered carbocycle-spiro-5-membered carbocyclyl, 4-membered carbocycle-spiro-6-membered carbocyclyl, 5-membered carbocycle-spiro-3-membered carbocyclyl, 5-membered carbocycl e-s pi ro-4-m embered carbocyclyl, 5-membered carb eye' e-spiro-5-membered carbocyclyl, 5-membered carbocycle-spiro-6-membered carbocyclyl, 6-membered carbocycle-spiro-3-membered carbocyclyl. 6-membered carbocycle-spiro-4-membered carbocyclyl, 6-membered carbocycle-spiro-5-membered carbocyclyl, 6-membered carbocycle-spiro-6-membered carbocyclyl, 3-membered carbocycle-spiro-3-membered heterocyclyl, 3-membered carbocycle-spiro-4-membered heterocyclyl, 3-membered carbocycle-spiro-5-membered heterocyclyl, 3-membered carbocycle-spiro-6-membered heterocyclyl, 4-membered carbocycle-spiro-3-membered heterocyclyl, 4-membered carbocycle-spiro-4-membered heterocyclyl, 4-membered carbocycle-spiro-5-membered heterocyclyl, 4-membered carbocycle-spiro-6-membered heterocyclyl, 5-membered carbocycle-spiro-3-membered heterocyclyl, 5-membered carbocycle-spiro-4-membered heterocyclyl, 5-membered carbocycle-spiro-5-membered heterocyclyl, 5-m embered carboeycle-spiro-6-m embered heterocyclyl, 6-membered carbocycle-spiro-3-membered heterocyclyl, 6-membered carbocycle-spiro-4-membered heterocyclyl, 6-membered carbocycle-spiro-5-membered heterocyclyl, 6-membered carbocycle-spiro-6-membered heterocyclyl, 3-membered heterocycle-spiro-3-membered carbocyclyl, 3-membered heterocycle-spiro-4-membered carbocyclyl, 3-membered heterocycle-spiro-5-membered carbocyclyl, 3-membered heterocycle-spiro-6-m embered carbocyclyl, 4-membered heterocycle-spiro-3-membered carbocyclyl, 4-membered heterocycle-spiro-4-membered carbocyclyl, 4-membered heterocycle-spiro-5-membered carbocyclyl, 4-membered heterocycle-spiro-6-membered carbocyclyl, 5-membered heterocycle-spiro-3-membered carbocyclyl, 5-membered heterocycle-spiro-4-membered carbocyclyl, 5-membered heterocycle-spiro-5-membered carbocyclyl, 5-membered heterocycle-spiro-6-membered carbocyclyl, 6-membered heterocycle-spiro-3-membered carbocyclyl, 6-membered heterocycle-spiro-4-membered carbocyclyl, 6-membered heterocycle-spiro-5-membered carbocyclyl, 6-membered heterocycle-

- 12 -spiro-6-membered carbocyclyl, 3-membered heterocycle-spiro-3-membered heterocyclyl, 3-membered heterocycle-spiro-4-membered heterocyclyl, 3-membered heterocycle-spiro-5-membered heterocyclyl, 3-membered heterocycle-spiro-6-membered heterocyclyl, 4-membered heterocycle-spiro-3-membered heterocyclyl, 4-membered heterocycle-spiro-4-membered heterocyclyl, 4-membered heterocycle-spiro-5-membered heterocyclyl, 4-membered heterocycle-spi ro-6 -m emb ered heterocyclyl, 5-membered heterocycl e-spiro-3-m embered heterocyclyl, 5-membered heterocycle-spiro-4-membered heterocyclyl, 5-membered heterocycle-spiro-5-membered heterocyclyl, 5-membered heterocycle-spiro-6-membered heterocyclyl, 6-membered heterocycle-spiro-3-membered heterocyclyl, 6-membered heterocycle-spiro-4-membered heterocyclyl, 6-membered heterocycle-spiro-5-rnernbered heterocyclyl, or 6-membered heterocycle-spiro-6-membered heterocyclyl; the carbocyclyl and heterocyclyl are optionally further substituted with 1, 2 or 3 RA substituents; unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S
and 0;
RA is selected from deuterium, halogen, amino, cyano, hydroxyl, C16 alkyl, halo C16 alkyl, deuterated C16 alkyl, C16 alkoxy, halo C16 alkoxy, deuterated alkoxy, or hydroxy C I -6 alkyl; in certain embodiments, RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1_4 alkyl, halo C14 alkyl, deuterated C1-4 alkyl, C1_4 alkoxy, halo C14 alkoxy, deuterated C14 alkoxy, or hydroxy C1_4 alkyl;
in certain embodiments, RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C12 alkyl, halo C1_2 alkyl, deuterated C1_2 alkyl, C1_2 alkoxy, halo alkoxy, deuterated C 1 -2 alkoxy, or hydroxy C 1 -2 alkyl; unless otherwise specified, the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0, R51 ,R32 R*1 02 ' provided that when Z is selected from 0, R41 R42 R61 does not form the following structures:

H 2N and In particular, as a first technical solution of the present invention, the present invention relates to a compound of formula (I), or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,

- 13--x2, )(,3 2(1. ,R2 R1 ')C4 ,R32 R51 ,R52 \

R61 (I) wherein X1, X2, X3 and X4 arc each independently selected from N or CRx;
Yi, Y2 and Y3 are each independently selected from N or CRY;
5 Z is selected from NR' or 0;
R' is selected from 11, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, or deuterated CI-6 alkyl;
Rx and RY are each independently selected from H, deuterium, halogen, amino, nitro, cyano, hydroxyl, sulphonyl, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 10 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, deuterated C1-6 alkoxy, hydroxy C1-6 alkyl, C3-6 cycloalkyl, or 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA;
RI and R2 are each independently selected from H, deuterium, halogen, 15 amino, -COOT-I, cyano, sulphonyl, aminoacyl, C1_6 alkyl, halo Ci_6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo C1_6 alkoxy, deuterated CI-6 alkoxy, hydroxy C1-6 alkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, -NT-TC(0)Ci_6 alkyl, -NT-TC(0)C3-6 cycloalkyl, -NHC(0)C4_6 heterocycloalkyl, -NT-TC(0)NT-ICi_6 alkyl, or -20 NHC(0)0C1_6 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA;
R3I and R32 are each independently selected from I-I, deuterium, halogen, cyano, hydroxyl, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; or R3I and R32 together 25 with the carbon atom to which they are attached form C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents;
R4I and R42 arc each independently selected from H, deuterium, amino, C1-6 30 alkyl, halogen, cyano, hydroxyl, halo C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy,

- 14 -halo C1-6 alkoxy, -C1_6 alkyl-C3_6 cycloalkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, deuterated CI-6 alkoxy, or hydroxy C1-6 alkyl;
or R41 and R42 together form C36 cycloalkyl or 4- to 6-membered 5 heterocycloalkyl containing 1 heteroatom selected from 0 or S, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA

substituents;
R51 and R52 are each independently selected from I-I, deuterium, amino, halogen, C1-6 alkyl, cyano, hydroxyl, halo C1_6 alkyl, deuterated CI _6 alkyl, 10 alkoxy, halo C1_6 alkoxy, -C1_6 alkyl-C3_6 cycloalkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; or R51 and R52 together with the carbon atom to which they are attached form C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the

15 cycloalkyl and heterocycloalkyl are optionally further substituted with substituents;
R61, R62 and R63 are each independently selected from I-I, deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, halo C1_6 alkyl, deuterated C1-6 alkyl, C1-alkoxy, halo C1-6 alkoxy, -C1_6 alkyl-C3_6 cycloalkyl, C3-6 cycloalkyl, 4- to 20 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S
and 0, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl:
or, R31 and R41. or R41 and R51 together with the carbon atoms to which they are each attached form C3_6 cycloalkyl or 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the cycloalkyl and 25 heterocycloalkyl are optionally further substituted with 1-3 RA
substituents;
or, R41 and R61, or R' and R41 together with the atoms to which they are each attached form C4-6 cycloalkyl or 4- to 6-membered heterocycloalkyl containing heteroatoms selected from N, S and 0, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents;
30 or, R51 and R61, or R61 and R62 together with the carbon atom(s) to which they are each attached form C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, or a double bond, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-substituents;

or, R61, R62 and R63 together with the carbon atom to which they are attached form C5-10 bridged ring, or C5-11 Spiro ring, wherein the bridged ring and Spiro ring are optionally further substituted with 1-3 RA substituents;
RA is selected from deuterium, halogen, amino, cyano, hydroxyl, C16 alkyl, 5 halo C1-6 alkyl, deuterated CI-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl, provided that when Z is selected from 0, R61 does not form the following structures:
andH2N

10 As a second technical solution of the present invention, the present invention relates to a compound of formula (Ia), or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof N

y ). R62 R61 (la).
As a third technical solution of the present invention, the present invention 15 relates to the compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, wherein RI is selected from sulphonyl, aminoacyl, halo C1-3 alkyl, -NHC(0)C1_4 alkyl, -NHC(0)C3_6 cycloalkyl, -NHC(0)C4_6 heterocycloalkyl, -NHC(0)NHCI _4 alkyl, 20 or -NHC(0)0C1_4 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents;
R2 is selected from cyano, C1_3 alkyl, halo CI _3 alkyl, or deuterated Ci _3 alkyl;
RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1-3 alkyl, halo CI-3 alkyl, deuterated CI-3 alkyl, CI-3 alkoxy, halo CI-3 alkoxy, deuterated 25 alkoxy, or hydroxy CI _1 alkyl;
other groups have the same definitions as those in the preceding technical solutions.

- 16 -As a fourth technical solution of the present invention, the present invention relates to the compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, having a structure of formula (II):
Nõ HF2 5 R81 (II) other groups have the same definitions as those in the technical solutions described above.
As a fifth technical solution of the present invention, the present invention relates to the compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, wherein Z is selected from NR' or 0;
Rz is selected from H, deuterium or C1_4 alkyl;
R31 and R32 are each independently selected from H, deuterium, F, Cl, cyano, 15 hydroxyl, CI _4 alkyl, halo C1_4 alkyl, deuterated C1_4 alkyl, C1_4 alkoxy, halo C 1 -4 alkoxy, deuterated C1_4 alkoxy, or hydroxy C1_4 alkyl; or R31 and R32 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, or 5-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are 20 optionally further substituted with 1, 2 or 3 substituents selected from RA, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0;
R41 and R42 are each independently selected from H, deuterium, amino, C1-4 alkyl, halogen, cyano, hydroxyl, halo C1_4 alkyl, deuterated C14 alkyl, C14 alkoxy, halo C1_4 alkoxy, -C1_4 alkyl-3-membered cycloalkyl, -C1_4 alkyl-4-membered 25 cycloalkyl, -Ci_4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl. 6-membered heterocycloalkyl, deuterated C14 alkoxy, or hydroxy C 1 -4 alkyl; or R41 and R42 together form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, or 30 5-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are

- 17 -optionally further substituted with 1, 2 or 3 substituents selected from RA, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0;
R51 and R52 are each independently selected from H, deuterium, amino, halogen, C14 alkyl, cyano, hydroxyl, halo CI 4alkyl, deuterated C14 alkyl, C14 5 alkoxy, halo C1-4 alkoxy, -C1-4 al ky1-3-m emb ered cycloalkyl, -C1_4 alkyl-4-membered cycloalkyl, -C1_4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloal kyl , 4-membered h eterocycl alkyl , 5-membered heterocycloalkyl. 6-membered heterocycloalkyl, deuterated C1-4 alkoxy, or hydroxy C1_4 alkyl; or R51 and R52 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 substituents selected from RA, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0;
15 R61, R62 and R63 are each independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C1_4 alkyl, halo C1_4 alkyl, deuterated C 1_4 alkyl, alkoxy, halo C14 alkoxy, -C14 alkyl-3-membered cycloalkyl, -C14 alkyl-4-membered cycloalkyl, -C1_4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-20 membered heterocycloalkyl. 6-membered heterocycloalkyl, deuterated CI _4 alkoxy, or hydroxy Ci_4alkyl, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0;
or, R31 and R41. or R41 and R51 together with the carbon atoms to which they are each attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-25 membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 substituents selected from RA, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0;
30 Or, R41 and R61 together with the carbon atom(s) to which they are each attached form 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are

- 18 -optionally further substituted with 1, 2 or 3 substituents selected from RA, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0;
or, R7 and R41 together with the carbon atom(s) to which they are each attached form 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-5 membered heterocycloalkyl, wherein the heterocycloalkyl is optionally further substituted with 1, 2 or 3 substituents selected from RA and contains 1-3 heteroatoms selected from N, S and 0;
or, R51 and R61, or R61 and R62 together with the carbon atom(s) to which they are each attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, or a double bond, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA
substituents, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S
and 0;
15 or, R61, R62 and R63 together with the carbon atom to which they are attached form 5-membered bicyclic bridged ring, 6-membered bicyclic bridged ring, 7-membered bicyclic bridged ring, 8-membered bicyclic bridged ring. 5-membered spiro ring, 6-membered spiro ring, 7-membered spiro ring, 8-membered spiro ring, 9-membered spiro ring, or 10-membered spiro ring, wherein the bridged ring and 20 spiro ring are optionally further substituted with 1, 2 or 3 substituents selected from RA, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S
and 0;
RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1_4 alkyl, halo C1-4 alkyl, deuterated C1_4 alkyl, C1_4 alkoxy, halo C1_4 alkoxy, deuterated 25 alkoxy, or hydroxy C1_4 alkyl;
other groups have the same definitions as those in the preceding technical solutions.
As a sixth technical solution of the present invention, the present invention relates to the compound, or the stereoisomer, deuterated compound, solvate, 30 prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, having a structure of formula (Ib):

N
= I, ,R62 H2N R"
wherein R1 is selected from halo C1-3 alkyl, -NIC(0)Ci _4 alkyl, -NIC(0)C3-6 cycloalkyl, -NHC(0)C4-6 heterocycloalkyl, -NITC(0)NHCi_4 alkyl, or -NHC(0)0C1_4 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are 5 optionally further substituted with 1-3 substituents selected from deuterium, F, Cl, amino, cyano, or hydroxyl;
R2 is selected from cyano, halo CI -3 alkyl, or deuterated CI -3 alkyl;
R51 and R52 are each independently selected from H or deuterium;
R61 is independently selected from H, deuterium, halogen, amino. cyano, 10 hydroxyl, CI _6 alkyl, halo CI _6 alkyl, deuterated CI _6 alkyl, CI -6 alkoxy, halo CI -6 alkoxy, -C1_6 alkyl-C3_6 cycloalkyl, C1_6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, deuterated CI -6 alkoxy or hydroxy CI -6 alkyl;
R62 and R63 are each independently selected from halogen, amino, cyano, 15 hydroxyl, CI -6 alkyl, halo C1 -6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, -Ci.o alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, deuterated CI 6 alkoxy, or hydroxy C1-6 alkyl;
or, R61 and R62 together with the carbon atom(s) to which they arc each 20 attached form C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, or a double bond, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 substituents selected from deuterium, F, Cl, amino, cyano, or hydroxyl.
As a seventh technical solution of the present invention, the present invention 25 relates to the compound of formula (I), (Ia), (Ib) or (II), or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, wherein R1 is selected from halo Ci_3 alkyl, -NTC(0)Ci_4 alkyl, -NIC(0)C3-6 cycloalkyl, or -NHC(0)0Ci -4 alkyl, wherein the alkyl, cycloalkyl and 30 heterocycloalkyl are optionally further substituted with 1-3 substituents selected from deuterium, F, Cl, amino, cyano, or hydroxyl; in certain embodiments. R1 is selected from halo C1-3 alkyl, or -NHC(0)0C1_4 alkyl; in certain embodiments, is selected from -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF7CH2F, -CF2CHF2, -CF2CF3, -NHC(0)CH3, F>L=7) N =
= -NHC(0)0CH3, F H or F F
5 R2 is selected from cyano or halo C1-3 alkyl; in certain embodiments, R2 is selected from cyano, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F. -CF2CHF2, or -CF2CF3; in certain embodiments, R2 is selected from cyano or -CTF); in certain embodiments, R2 is selected from -CHF2;
10 R51 and R52 are each independently selected from T-I or deuterium;
R61 is independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C1_3 alkyl, or hydroxy C1_3 alkyl; in certain embodiments, R61 is independently selected from H, deuterium, F, Cl, amino, cyano, hydroxyl, methyl, ethyl, -CH2OH, or -CH2CH2OH;
15 R62 and R63 are each independently selected from halogen, amino, cyano, hydroxyl, C1-3 alkyl, halo C1-3 alkyl, deuterated C1_3 alkyl, or hydroxy C1_3 alkyl; in certain embodiments, R62 and R63 are each independently selected from F, Cl, amino, cyano, hydroxyl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -20 CF2CF3, -CH2D, -CHD2, -CD3, -CH2CH7D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3, -CH,OH, or -CH-,CH2OH;
or, lel and R62 together with the carbon atom(s) to which they are each attached form C3, C4, C5, or C6 cycloalkyl or a double bond, wherein the cycloalkyl 25 is optionally further substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, amino, cyano, or hydroxyl.
As an eighth technical solution of the present invention, the present invention relates to the compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof 30 according to the present invention, wherein Z is selected from NR7 or 0;
R' is selected from H, deuterium, methyl, ethyl, n-propyl, or isopropyl;

---"- 62 --R
, Rai R42 R61 is selected from the following groups:
F F

F

xC F3 F
H2Ni ' CF3 H2N

i , H2N ' 'NH2 FF
F F
-"---(7)---H2N H2N 'F
H2N ' F KD'7 F

H2N H2N ' 6 HN

F Ei2c.yN

(>r 'OH
H2N HO 0 Hoi H2N
\

\ / . s R62 /
OH
R4/1 µR42 FI2N \
Or R61 is selected from -'0H =

R3' R32 W1 R52 N

Or, R61 is Selected from:
For the compound of formula (I) according to the present invention, Xi, X2, X3 and X4 are each independently selected from N or CR"; in certain embodiments, Xi is selected from N, and X2, X3 and X4 are each independently selected from N
5 or CR"; in certain embodiments, Xi is selected from N, and X2, X3 and X4 are each independently selected from CR"; in certain embodiments, Xi is selected from CR", and X2, X3 and X4 are each independently selected from N or CR"; in certain embodiments, X2 is selected from N, and Xi, X3 and X4 are each independently selected from N or CR"; in certain embodiments, X3 is selected from N, and Xi, 10 and X4 are each independently selected from N or CR".
For the compound of formula (I) or (Ia) according to the present invention, Y2 and Y3 are each independently selected from N or CRY; in certain embodiments, Y1 is selected from N, and Y2 and Y3 are each independently selected from N or CRY; in certain embodiments, Yi is selected from N, and Y2 and 15 Y3 are each independently selected from CRY; in certain embodiments, Y2 is selected from N, and Yi and Y3 are each independently selected from CRY; in certain embodiments, Y3 is selected from N, and Yi and Y2 are each independently selected from CRY.
For the compound of formula (I), (Ia) or (II) according to the present 20 invention, Z is selected from NRz or 0; in certain embodiments, Z is selected from 0; in certain embodiments, Z is selected from Nit'.
For the compound of formula (I), (Ia) or (II) according to the present invention, Rz is selected from H, deuterium, halogen, C1-6 alkyl, halo C1-6 alkyl, or deuterated C1-6 alkyl; in certain embodiments, Rz is selected from H, deuterium, 25 halogen, C1_4 alkyl, halo C1_4 alkyl, or deuterated C1_4 alkyl; in certain embodiments, Rz is selected from H, deuterium, F, Cl, C1_2 alkyl, halo C1-2 alkyl, or deuterated C1_2 alkyl; in certain embodiments, Rz is selected from H, deuterium, F, Cl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CH2D, -30 CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, or -CD2CD3.

For the compound of formula (I) or (Ia) according to the present invention, Rx and RY are each independently selected from H, deuterium, halogen, amino, nitro, cyano, hydroxyl, sulphonyl, CI -6 alkyl, halo C1-6 alkyl, deuterated CI-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, deuterated C16 alkoxy. hydroxy C16 alkyl, C36 5 cycloalkyl, or C4-6 heterocycloalkyl; in certain embodiments, Rx and RY are each independently selected from H, deuterium, halogen, amino, nitro, cyano, hydroxyl, sulphonyl, Ci_4 alkyl, halo C1_4 alkyl, deuterated C1_4 alkyl, C1_4 alkoxy, halo C1-4 alkoxy, deuterated C1-4 alkoxy, hydroxy C1_4 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl. or 6-membered heterocycloalkyl; in certain embodiments, Rx and RY are each independently selected from H, deuterium, F, Cl, amino, nitro, cyano, hydroxyl, sulphonyl, alkyl, halo C1_2 alkyl, deuterated C1_2 alkyl, C1_2 alkoxy, halo C1_2 alkoxy, deuterated C1_2 alkoxy, hydroxy C1_2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0, and the alky, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA.
20 For the compound of formula (I), (la), (lb) or (II) according to the present invention, RI and R2 are each independently selected from H, deuterium, halogen, amino, -COOH, cyano, sulphonyl, aminoacyl, C1-6 alkyl, halo C1_6 alkyl, deuterated C1-6 alkyl, C1_6 alkoxy, halo C1_6 alkoxy, deuterated C1-6 alkoxy, hydroxy C1-6 alkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing heteroatoms selected from N, S and 0, -NHC(0)C 1_6 alkyl, -NHC(0)C3-6 cycloalkyl, -NHC(0)C4_6 heterocycloalkyl, -NHC(0)NHC1_6 alkyl, or -NHC(0)0C1_6 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents; in certain embodiments, RI
and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, 30 cyano, sulphonyl, aminoacyl, C1_4 alkyl, halo C1_4 alkyl, deuterated C1_4 alkyl, C1-4 alkoxy, halo C1_4 alkoxy, deuterated C1_4 alkoxy, hydroxy C1_4 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(0)C1_4 alkyl, -NT-IC(0)C36 cycloalkyl, -NHC(0)C4_6 heterocycloalkyl, -NHC(0)NHC1_4 alkyl, or -NHC(0)0C1_4 alkyl; in certain embodiments, RI and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulphonyl, aminoacyl, C1-2 alkyl, halo 2 alkyl, deuterated C12 alkyl, C12 alkoxy, halo C1_2 alkoxy, deuterated C12 alkoxy, 5 hydroxy C1-2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl. 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NT-TC(0)C1_2 alkyl, -NT-TC(0)C34 cycloalkyl, -NHC(0)C4_5 heterocycloalkyl, -NHC(0)NHC1_2 alkyl, or -NHC(0)00 _2 alkyl; in certain embodiments, RI and R2 are each independently 10 selected from H, deuterium, cyano, halo C1-2 alkyl, halo C1_2 alkoxy, -NT-IC (0)C12 alkyl, -NI-IC(0)0C12 alkyl, or -NHC(0)C3_4 cycloalkyl; in certain embodiments, RI and R2 are each independently selected from cyano, halo C1_2 alkyl, -NHC(0)C1_2 alkyl, -NHC(0)0C1_2 alkyl, or -NHC(0)C3_4 cycloalkyl; in certain embodiments, RI and R2 are each independently selected from cyano, -Cl2F, -15 CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, F>cr-J1-N--CF2CH2F, -CF2CHF2, -CF2CF3, -NHC(0)CH3, -NHC(0)0CH3, F

V , or Fi F
; in certain embodiments, RI and R2 are each independently selected from H, deuterium, halogen, amino, -COOH, cyano, sulphonyl, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl. C1-6 alkoxy, halo C1-6 20 alkoxy, deuterated C1_6 alkoxy, hydroxy C1_6 alkyl, C3-6 cycloalkyl, C4-6 heterocycloalkyl, -NHC(0)C1_6 alkyl, or -NHC(0)0C1_6 alkyl; in certain embodiments, RI and R2 are each independently selected from H, deuterium, F, Cl, amino, -COOH, cyano, sulphonyl, C1_4 alkyl, halo C1-4 alkyl, deuterated C1_4 alkyl, C1-4 alkoxy, halo C1-4 alkoxy, deuterated C1-4 alkoxy, hydroxy C1-4 alkyl, 3-25 membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(0)C1_4 alkyl, or -NHC(0)0C1-4 alkyl; in certain embodiments, RI and R2 are each independently selected from H. deuterium, F, Cl, amino, -COOH, cyano, sulphonyl, C1_2 alkyl, 30 halo C1_2 alkyl, deuterated C1_2 alkyl, C1_2 alkoxy, halo C1_2 alkoxy, deuterated C1-2 alkoxy, hydroxy C1-2 alkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -NHC(0)C1 -2 alkyl, or -NHC(0)0C1-2 alkyl; in certain embodiments, RI and R2 are each independently selected from deuterium, halo C12 alkyl, or halo C12 alkoxy; in certain 5 embodiments, R1 and R2 are each independently selected from halo C1-2 alkyl; in certain embodiments, RI and R2 are each independently selected from -Cl-12F, -CHF2, -CF3, -CT-LCH,F, -CT2CHF2, -C1-42CF3, -ClFCH,F, -CHFCHF2, -CIFCF3, -CF2CH2F, -CF2CHF2, or -CF2CF3, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0, wherein the alkyl, cycloalkyl and 10 heterocycloalkyl are optionally further substituted with 1-3 RA.
For the compound of (I), (Ta), (Ib) or (II) according to the present invention, RI is selected from sulphonyl, aminoacyl, halo C1-6 alkyl, -NTIC(0)C1_6 alkyl, -NHC(0)C3.6 cycloalkyl, -NHC(0)C4.6 heterocycloalkyl, -NHC(0)NHC1_6 alkyl, or -NI-IC(0)0C16 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are 15 optionally further substituted with 1-3 RA substituents; in certain embodiments, RI
is selected from sulphonyl, aminoacyl, halo C1-3 alkyl, -NHC(0)C1_4 alkyl, -NHC(0)C3 6 cycloalkyl, -NI-IC(0)C46 heterocycloalkyl, -NHC(0)NHC1 4 alkyl, or -NIC(0)0C1.4 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA substituents; in certain 20 embodiments, RI is selected from sulphonyl, aminoacyl, halo C1.2 alkyl, -NHC(0)C1-2 alkyl, -NT-IC(0)C34 cycloalkyl, -NHC(0)C4_5 heterocycloalkyl, -NHC(0)NHC1_2 alkyl, or -NHC(0)0C1_2 alkyl; in certain embodiments, RI is selected from halo C1_2 alkyl. -NHC(0)C1_2 alkyl, -NHC(0)0C1_2 alkyl, or -NHC(0)C3_4 cycloalkyl; in certain embodiments, RI is selected from -CH2F, -25 CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, F>it'N
-CF2CH2F, -CF2CHF2, -CF2CF3, -NHC(0)CH3, -NHC(0)0CH3, F
0 jOi H or F F
For the compound of formula (I). (Ia), (Ib), or (II) according to the present invention, R2 is selected from cyano, C1-6 alkyl, halo C1-6 alkyl, deuterated 30 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, deuterated C1-6 alkoxy, hydroxy C1-6 alkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents; in certain embodiments, R2 is selected from cyano, C1-4 alkyl, halo C1-4 alkyl, or deuterated C1-4 alkyl;
in certain embodiments, R2 is selected from cyano, C1_2 alkyl, halo C12 alkyl, or 5 deuterated C1-2 alkyl; in certain embodiments, R2 is selected from cyano, CI-2 alkyl, or halo C1_2 alkyl; in certain embodiments, R2 is selected from cyano, -CH3, -CH2C1-13, -ClF,, -CF3, -CH,CH,F, -CH2CF3, -CT-1FCH2F, -CHFCHF2, -CIFCF3, -CF2CH2F, -CF2CHF2, or -CF2CF3.
For the compound of formula (I), (la) or (II) according to the present 10 invention, R31 and R32 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, C1-6 alkyl, halo C1_6 alkyl, deuterated C1_6 alkyl, alkoxy, halo C1-6 alkoxy, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; or R31 and R32 together with the carbon atom to which they are attached form C3_6 cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl 15 are optionally further substituted with 1-3 RA substituents; in certain embodiments, R31 and R32 are each independently selected from H, deuterium, F, Cl, cyano, hydroxyl, C14 alkyl, halo C14 alkyl, deuterated C1_4 alkyl, C14 alkoxy, halo alkoxy, deuterated C1_4 alkoxy, or hydroxy C 1_4 alkyl, or R31 and R32 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-20 membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl. or 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA substituents; in certain embodiments, R31 and R32 are each independently selected from H, deuterium, F. Cl, hydroxyl, C1_2 alkyl, 25 halo C1-2 alkyl, deuterated C12 alkyl, C1_2 alkoxy, halo C1_2 alkoxy, deuterated C1-2 alkoxy, or hydroxy C1_2 alkyl, or R31 and R32 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, or 4-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA substituents, and the 30 heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0.
For the compound of formula (I), (la) or (II) according to the present invention, R41 and R42 are each independently selected from H, deuterium, amino, CI _6 alkyl, halogen, cyano, hydroxyl, halo C1-6 alkyl, deuterated CI -6 alkyl, CI -6 alkoxy, halo C16 alkoxy, -C1_6 alkyl-C3_6 cycloalkyl, C3_6 cycloalkyl, C4-6 heterocycloalkyl, deuterated C16 alkoxy, or hydroxy C16 alkyl; in certain embodiments, R41 and R42 are each independently selected from H, deuterium, amino, C1-4 alkyl, halogen, cyano, hydroxyl, halo C 1 -4 alkyl, deuterated C1-6 alkyl, CI-4 alkoxy, halo C14 alkoxy, -C1-4 alkyl-3-membered cycloalkyl, -C14 alkyl-4-5 membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-m emb ered h et ero cy cl oal kyl , 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C 1 -4 alkoxy, or hydroxy C1_4 alkyl; in certain embodiments, R41 is selected from H, deuterium, amino, C 1 -4 alkyl, halogen, 10 cyano, hydroxyl, halo C1-4 alkyl, deuterated C1_6 alkyl, C1_4 alkoxy, halo C1-4 alkoxy, -C1_4 alkyl-3-membered cycloalkyl, -C1_4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, 15 deuterated C1_4 alkoxy, or hydroxy C1_4 alkyl; in certain embodiments, R41 is selected from H, deuterium, amino, C1-4 alkyl, halogen, cyano, hydroxyl, halo C1_2 alkyl, deuterated C12 alkyl, C12 alkoxy, halo C12 alkoxy, -C12 alkyl-3-membered cycloalkyl, -C1_2 alkyl-4-membered cycloalkyl, -C1_2 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-20 membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1_2 alkoxy, or hydroxy C1_2 alkyl; in certain embodiments, R42 is selected from H, hydroxyl, amino, C1_2 alkyl, deuterated C1-2 alkyl, or C1-2 alkoxy; in certain embodiments, R42 is selected from amino, and the heterocycloalkyl contains 1-3 heteroatoms selected 25 from N, S and O.
For the compound of formula (I), (la) or (II) according to the present invention, R41 and R42 together form C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl containing 1 heteroatom selected from 0 or S. wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA
30 substituents; in certain embodiments, R41 and R42 together form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, or 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl containing 1 heteroatom selected from 0 or S.
wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA substituents.
For the compound of formula (I). (Ia), (Ib), or (II) according to the present invention, R5' and R52 are each independently selected from H, deuterium, amino, 5 halogen, C1-6 alkyl, cyano, hydroxyl, halo C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, -C1_6 alkyl-C3_6 cycloalkyl, C3-6 cycloalkyl, C4-6 heterocycloalkyl, deuterated C _6 alkoxy, or hydroxy CI _6 alkyl; or R51 and together with the carbon atom to which they are attached form C3_6 cycloalkyl or 4-to 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are 10 optionally further substituted with 1-3 RA sub stituents; in certain embodiments, R51 and R52 are each independently selected from H, deuterium, amino, F, Cl, C1-4 alkyl, cyano, hydroxyl, halo C1_4 alkyl, deuterated C1_4 alkyl, C1_4 alkoxy, halo C1-4 alkoxy, -C1_4 alkyl-3-membered cycloalkyl, -C1_4 alkyl-4-membered cycloalkyl, -C1-4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered 15 cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated CI 4 alkoxy, or hydroxy C14 alkyl; or R5' and R52 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered 20 heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA substituents; in certain embodiments, R51 and R52 are each independently selected from H, deuterium, amino, F, Cl, C1_4 alkyl, cyano, hydroxyl, halo C1_2 alkyl, deuterated C1_2 alkyl, C1_2 alkoxy, halo C1_2 alkoxy, -C1-2 25 alkyl -3-membered cycloalkyl, -C1_2 alkyl-4-membered cycloalkyl, -C1_2 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl. 6-membered heterocycloalkyl, deuterated CI-2 alkoxy, or hydroxy C1-2 alkyl, or R51 and R52 together with the carbon atom to which they 30 are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 4-membered heterocycloalkyl, or 5-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA
substituents; in certain embodiments, R51 and R52 are each independently selected from H, deuterium, amino, F, Cl, C1-4 alkyl, cyano, hydroxyl, halo C1_2 alkyl, or R5' and R52 together with the carbon atom to which they are attached form 3-membered cycloalkyl.
For the compound of formula (I). (Ia), (Ib), or (II) according to the present invention, R61, R62 and R63 are each independently selected from 14, deuterium, 5 halogen, amino, cyano, hydroxyl, C1-6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo C1-6 alkoxy, -C1-6 alkyl-C3_6 cycloalkyl, C3-6 cycloalkyl, heterocycloalkyl, deuterated C -6 alkoxy, or hydroxy C -6 alkyl; in certain embodiments, R61, R62 and R63 are each independently selected from H, deuterium, F, Cl, amino, cyano, hydroxyl, C1_4 alkyl, halo C14 alkyl, deuterated C1_4 alkyl, C1-4 10 alkoxy, halo C14 alkoxy, -C1_4 al ky1-3-m emb ered cycloalkyl, -C1_4 alkyl-4-membered cycloalkyl, -Ci_4 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1_4 alkoxy, or hydroxy C1_4 alkyl; in certain 15 embodiments, R61, R62 and R63 are each independently selected from H, deuterium, F, Cl, amino, cyano, hydroxyl, C1_2 alkyl, halo C1_2 alkyl, deuterated C1_2 alkyl, C1-2 alkoxy, halo C1_2 alkoxy, -C12 alkyl-3-membered cycloalkyl, -C12 alkyl-4-membered cycloalkyl, -C1_2 alkyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-20 membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, deuterated C1_2 alkoxy, or hydroxy C1_2 alkyl; in certain embodiments, R61, R62 and R63 are each independently selected from H, deuterium, F, Cl. amino, cyano, hydroxyl, methyl, ethyl, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -25 CF2CF3, -CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3, methoxy, ethoxy, -OCHF2, -OCH2F, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCHFCH2F, -OCHFCHF2, -OCHFCF3, -0CF2CH2F, -0CF2CHF2, -0CF2CF3, -methyl-3-membered cycloalkyl, -ethyl-3-membered cycloalkyl, -methyl-4-membered 30 cycloalkyl, -ethyl-4-membered cycloalkyl, -methyl-5-membered cycloalkyl, -ethyl-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, -OCHD2, -OCT-12D, -OCD3, -OCH2CH2D, -OCH2CHD2, -OCH2CD3, -OCTDCH2D, -OCHDCHD2, -OCHDCD3, -0CD2CH2D, -0CD2CHD2, -0CD2CD3, -CH2OH, or -CH2CH2OH, wherein the heterocycloalkyl contains 1-3 heteroatoms selected from N. S and 0.
For the compound of (I), (Ia) or (II) according to the present invention, R31 and R41, or R41 and R51 together with the carbon atoms to which they are each 5 attached form C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA

substituents; in certain embodiments, R31 and R41, or R41 and R51 together with the carbon atoms to which they are each attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl. or 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA substituents, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0.
For the compound of (I), (Ia) or (H) according to the present invention, R41 15 and R61, or Ri and R41 together with the atoms to which they are each attached form C4-6 cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA
substituents; in certain embodiments, R41 and R61, or R' and R41 together with the atoms to which they are each attached form 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, or 6-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA
substituents, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0.
For the compound of formula (I). (Ia), (Ib), or (II) according to the present 25 invention, R51 and R61, or R61 and R62 together with the carbon atom(s) to which they are each attached form C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, or a double bond, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents; in certain embodiments, R51 and R61, or and R62 together with the carbon atom(s) to which they are each attached form membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, 4-membered heterocycloalkyl, 5-membered heterocycloalkyl, 6-membered heterocycloalkyl, or a double bond, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA

substituents, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S
and 0.
For the compound of formula (I). (Ia), (Ib), or (II) according to the present ,=62 invention, R61, Kand R63 together with the carbon atom to which they are 5 attached form C5-10 bridged ring, or C5-11 spiro ring, wherein the bridged ring and spiro ring are optionally further substituted with 1-3 RA substituents; in certain embodiments, R61, R62 and R63 together with the carbon atom to which they are attached form 5-membered bridged ring, 6-membered bridged ring, 7-membered bridged ring, 8-membered bridged ring, 5-membered spiro ring, 6-membered spiro 10 ring, 7-membered spiro ring, 8-membered spiro ring, 9-membered spiro ring, 10-membered spiro ring, or 11-membered spiro ring, wherein the bridged ring and spiro ring are optionally further substituted with 1, 2 or 3 RA substituents;
in certain embodiments, R61, R62 and R63 together with the carbon atom to which they are attached form 5-membered saturated carbocyclic bridged ring, 6-membered 15 saturated carbocyclic bridged ring, 7-membered saturated carbocyclic bridged ring, 8-membered saturated carbocyclic bridged ring, 3-membered carbocycle-spiro-3-membered carbocyclyl, 3-membered carbocycle-spiro-4-membered carbocyclyl, 3-membered carbocycle-spiro-5-membered carbocyclyl, 3-membered carbocycle-spiro-6-membered carbocyclyl, 4-membered carbocycle-spiro-3-membered 20 carbocyclyl, 4-membered carbocycle-spiro-4-membered carbocyclyl. 4-membered carbocycle-spiro-5-membered carbocyclyl, 4-membered carbocycle-spiro-6-membered carbocyclyl, 5-membered carbocycle-spiro-3-membered carbocyclyl, 5-membered carbocycle-spiro-4-membered carbocyclyl, 5-membered carbocycle-spiro-5-membered carbocyclyl, 5-membered carbocycle-spiro-6-membered 25 carbocyclyl, 6-membered carboeyele-spiro-3-membered carbocyclyl, 6-membered carbocycle-spiro-4-membered carbocyclyl, 6-membered carbocycle-spiro-5-membered carbocyclyl, 6-membered carbocycle-spiro-6-membered carbocyclyl, 3-membered earbocycle-spiro-3-membered heterocyclyl, 3-membered earboeyele-spiro-4-membered heterocyclyl, 3-membered carbocycle-spiro-5-membered 30 heterocyclyl, 3-membered carbocycle-spiro-6-membered heterocyclyl, 4-membered carbocycle-spiro-3-membered heterocyclyl, 4-membered carbocycle-spiro-4-membered heterocyclyl, 4-membered carbocycle-spiro-5-membered heterocyclyl, 4-membered carbocycle-spiro-6-membered heterocyclyl, 5-membered carbocycle-spiro-3-membered heterocyclyl, 5-membered carbocycle-spiro-4-membered heterocyclyl, 5-membered carb ocycl e-spiro-5-m embered heterocyclyl, 5-membered carbocycle-spiro-6-membered heterocyclyl, 6-membered carbocycle-spiro-3-membered heterocyclyl, 6-membered carbocycle-spiro-4-membered heterocyclyl, 6-membered carbocycle-spiro-5-membered heterocyclyl, 6-membered carbocycle-spiro-6-membered heterocyclyl, 3-membered heterocycle-spiro-3-membered carbocyclyl, 3-membered heterocycle-spi ro-4-m emb ered carbocyclyl, 3-membered heterocycl e-spiro-5-membered carbocyclyl, 3-membered heterocycle- spiro-6-m embered carbocyclyl, 4-membered heterocycle-spiro-3-membered carbocyclyl, 4-membered heterocycle-spiro-4-membered carbocyclyl, 4-membered heterocycle-spiro-5-membered carbocyclyl, 4-membered heterocycle-spiro-6-membered carbocyclyl, 5-membered heterocycle-spiro-3-membered carbocyclyl, 5-membered heterocycle-spiro-4-mernbered carbocyclyl, 5-membered heterocycle-spiro-5-membered carbocyclyl, 5-membered heterocycle-spiro-6-membered carbocyclyl, 6-membered heterocycle-spiro-3-membered carbocyclyl, 6-membered heterocycle-spiro-4-membered carbocyclyl, 6-membered heterocycle-spiro-5-membered carbocyclyl, 6-membered heterocycle-spiro-6-membered carbocyclyl, 3-membered heterocycle-spiro-3-membered heterocyclyl, 3-membered heterocycle-spiro-4-membered heterocyclyl, 3-membered heterocycle-spiro-5-membered heterocyclyl, 3-membered heterocycle-spiro-6-membered h et erocycl yl , 4-m embered heterocycl e-spiro-3-membered heterocyclyl, 4-membered heterocycle-spiro-4-membered heterocyclyl, 4-membered heterocycle-spiro-5-membered heterocyclyl, 4-membered heterocycle-spiro-6-membered heterocyclyl, 5-membered heterocycle-spiro-3-membered heterocyclyl, 5-membered heterocycle-spiro-4-membered heterocyclyl, 5-membered heterocycle-spiro-5-membered heterocyclyl, 5-membered heterocycle-spiro-6-membered heterocyclyl, 6-membered heterocycle-spiro-3-membered heterocyclyl, 6-membered heterocycle-spiro-4-membered heterocyclyl, 6-membered heterocycle-spiro-5-membered heterocyclyl, or 6-membered heterocycle-spiro-6-membered heterocyclyl; the carbocyclyl and heterocyclyl are optionally further substituted with 1, 2 or 3 RA substituents, and the heterocycloalkyl contains 1-3 heteroatoms selected from N, S and 0.
For the compound of formula (I). (Ia), (Ib), or (II) according to the present invention, RA is selected from deuterium, halogen, amino, cyano, hydroxyl, CI
_6 alkyl, halo C1-6 alkyl, deuterated CI-6 alkyl, CI-6 alkoxy, halo C1-6 alkoxy, deuterated C1-6 alkoxy, or hydroxy C16 alkyl, in certain embodiments, RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1_4 alkyl, halo C1_4 alkyl, deuterated C1-4 alkyl, C1-4 alkoxy, halo C1-4 alkoxy, deuterated C1-4 alkoxy, or hydroxy CI 4alkyl; in certain embodiments, RA is selected from deuterium, F, Cl, 5 amino, cyano, hydroxyl, C1-2 alkyl, halo C1_2 alkyl, deuterated CI-2 alkyl, C1-2 alkoxy, halo CI _2 alkoxy, deuterated CI _2 alkoxy, or hydroxy C1_2a1ky1.
For the compound of formula (1), (la) or (II) according to the present R31 R. R61 R52 A. Re2 p 2 invention, when Z is selected from 0,R'' does not form the following structures:
`,"1,-----x-----,...--H2N ) 10 H2N and F .
The present invention provides the compound of formula (I), (Ia), (Ib), or (II), or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound has a structure selected from one of the following:
rii i N1, F
F 1,,II. ,-- its]; :F ..i,,:x F,T,F0 N I,F N- =-==
I F
Fy.,,,,,rk....F F ..-- N F
I' 0H7r----õ(CF, ;
H2r1---.- 0;Kii- F
F
4 N),, 1,1"- F

I Il 11, `rsi-- 'F I N' F I -II 'I CHF2 F
F

K ---,(CF3 F F k; '-"I '0''F
0 0' HA I H21,1 CF, H2/,---ri< H2N `F-1-"F
N'-`" /1 ;13 F N''''''', F A ..- N. 1 FHN,:, F,,i .
..'" N:f.,F
F-' F
y F F I
..7 .....,,T_ ---15 ric; -- 'r' H2N -0---7( H2N , 1 11 ,. N I NC /1 N Fi F 1 , NI.' 7 F
,r.-1-, 1 F F
F
F-F F I
'='0 F ' 0- , (-. 0 \
Hie \ --" H21,1 H2N
N', F isl"-= F
N ''..)- ,I. rL N''- F
F NF F F
I ,/ N F x.J.,F F
I .., N,.1.-1.F
F I .,...- crõ.x..\y,,..õ F
0-'-'7,------'-r.,,F F I --- -H2N I H2N\ 1./"\F
H2N \ L.
-..
1111 ''l F 10, N ,I N.---') F --t-,.
N , F
1 F. -1!. --- .N ..1.
F I ,--= N,, F
F N
,r ,-- yl,Xo'F 0 F I
F .-, ...õ 0;-1-2I'NX-y F
..-- c):::r.r--..
H2N' \ I H2N
..-. ..-, N '- N'''', n ..- F
F
F
, -7 F
H2N ,--__/
1;1)\--- H2N F
H2C-K) N''-- F
12,T)1, F N' )--., F
F N F ' ....-- Nz.T.J., F -L; ...- yrNõI.-1,F N '", F
, 1---LT F

1 F ..--- NIõ,....LF
F F
., .Ø.,-...,< --_, -)c--h F [Iv --,0 I
H2N N----j H2N Lo H24 F N'.-1 N'i N --.
'-'1 F .II. ..-= - N .1... F 1A N CHF2 F )1 ..-A. N .CHF2 F I , N2x-LF
'''"nr VII " ''= -.--1--I ..--- 01..5.1 .2is(?.c, 0 , N" 'N F N N- F N ."== F Ni F
F (IL,- N F 1 N F I
, , F
I
;1 F I F I _ I 0-'''F
'',,,,_, cF, F

---....-- = --.,..-- ----..---- -..
F
H2N ' ' I H2N
H24 ' I
N ."--- F N ---ki F N-------H. N" ''''-i F
F F 11. ....- N 1 F
,1].. ..--). N, .CHF2 F. ,J, , N J-1 X Uct'F ''.
X LT j,0 F
..-- ...--õK-A
N-'n-z 1 H2N , N , F N''. F

F
F N '--I F
o I
I I F
..7 Ny-LF
C(-N?<I, F ..., I
H2N ' ---- ...w.i,-ll.:21:17'cl' -I
0 N'' , 0 N '''''''', o 1 F F
F
F o N F
AN CN
"I'L'N"-J-= i'ao'', C.: \,,,,,,,,I( '0 U 1 11 L.õF
-0"N------------ry-õ,---..., ..--- ..)\.õ---,i-H2N \ H2N H2N

O N.----'1, F 0 ..,N, 2,-...,,T. 1 F IT).- . N. ...1.
J. I N ., o N , --.-1.-- ---.0)tis, --- ,, CHF2 H 1 Uo 'F
r-i-''' In( F H
'-' 0,....;.>\õ....õ( '"O'''''A!' '0---- -7,-----e.
-----K---'COH

1-13N µ 1 H2N y Ni F N
FT,,..,(I.; F 1I,F
..-- N..,,CHF2 I
FT-21:r<1.---0 N '''--- 0 N - 0 1 F 0 1 -;-21:101--- H2N µF H2NII

Ci) 11 0 N ---- 0 ..ir.).3i F
=-... ..-11,. I -, CHF2 '-'0,1 V , 1.1..-X)'F 5,) _C-- . ,...r.cHF2 ,c) N o N -...
H 1 0 N 1 i -`N 01.1'2N)c ------(= N 0---)<\---1<;14.,...,..1..Ø..

H2N I H2N ' I
0 N'C'IT, .,,,,,) 0 N.-. 1 F.,, I? N,..! 1 ' QIN 1 , N---y' )1'14-j- '`.. NH2 F>c7,),N -...
,..,õ.õ,(CN
-'''''N H
. CoN
I
X-1G-F ...1 F
-- X -T-H,N µ I r H2N ', H3N II 1.1211C T
D N '"-- 0 N'I'll 0 F,ro, ,N, ,FLF
..Ø.11-.N CF3 F 11, I H
NI,,,, 0 --- _Hy I' f,L .-- =
^ -' H
-D-H'Z''-'V NF I . H2N? 1r N(',33HH

"--,-,-,-.

I
--.0 -----t N ------.. N
1 '-j''F
H
H2N y \ .
The compound has a structure further selected from:

¨ 35 -N ."-- F
I I N- u'uN F
F ..--- N,r-1...F , --,-F F ..., NI-1,F
F. -11,. ...-- . N .,I, F I I
--- ..--,...----.. ,..---.. F
I uu y ----' 1 ---y 'F
u'l uuNuu,F F
- FIX N I F -, 0--uu,-iciy F CF, H2N FIX = I ...-CH2N.rr u'F
NI F N -'-- F
=== J-, N .,. F
õ.õ-1,(,,,,x,..-=
N.õ CHF2 .L.,Fi, F ..--- N F N F F FK.2....,F
F-I, F I ., FXF F0"-A-uu F
H. 21iS I Figsf cFs ;V< H2N
F F
N N"."'--",-- F r,y2ar. F VD-. , 1.--- N F. -"Le N ul F ' õ..-= N.1,1õF F. ,..1t, ..,--.õN.õCHF2 F
Fy1,41 ..7.,F --T" ----`r ,r,. , u-F
1 ;
F I 7 . V F F
N 11 12NT '13Fiu 11-14--i- 2N
N'' F N- F NA-m--, F N ', F
F.õ....-11 ,-J-.. .N . .1.- F. )1.N. -1,.. F,y..1: u.- ...- .N .
.J.
I Tt.,:_j F F -/¨ - - --r --r-, , F
F]--.....c.N ,-1..F \ _ I
F 0-('''= F U...õ,--..-(..0,---,<1....õ,õ, ___ F U--õ,A.--= Ø.--... \.----- F

F2N = ---- H2N' H2hr F N ''',. F
N "-- F N '--- F
F . 0 N I Fyltõ..õ, .õCµJ1-..F
'r ,. F I F õr-lj. .-.' .D--',..,,N..,_.,),..F F.õõ ..xl..N., F
I
F -- 0.. ,-..K-u.T.,-. F 0--'Nuu,,<F F I
..--.0,--.x..7, F
N'u.
H2N H2N = F I-120 N -", F N -- '')-- F õin F F
F.õ.õ:F Fyil,F N -LF F.õ.õ-I-I,-Nõ.õ--1, F I F
0"----s; -T- H2N
c'A
KI-1-1--0, 'r- ' HA I '-1.-14-1-12 Ni F N -", F N--')- ' õuu F
[I I
N F F , ...1., ,F1J-1, F..,,,,-- ,_,N,,,J...c FF-- F
I ,,,..1 uuu, u F ..- N......F
F '0- X-7 ""-'-'`,0 ,0,3 1 , .õ
.2.- H2ri ''S),---F .2.
.2.-,, 1 N-u-')õ F N =-=-'1,õ(_,..xF Fr'-'1u:
y. .N, .L.F F.,,,,,Qõ,,,- N, -1,,F
Fr .--)õ F
I I I F I F, -11.
.." A, .1...
F Lu--.1.-euuu F .---- 0õ.....õ..õ..õ--F1õ,,..3õ .F
Hei H20 L-c{, H2N 0 F
N '--- F N ---, N--'-ki isr- F
Fyitõ.7,1,,C2xCHF2 I F 1 i N.õ F F N., CHF2 F
I I I
F
F
H2Nx H2N Ole' 07C1' H2N"
N '", F N".... F 1,1 `...
N ''', F
F I .7 N F ...1, .." ,N, u-I... F.õ õa õN., .,..7.,F
I f F1,.T F I .1, 1 F , 0,--...4,--,õCF2 F --, .."...T.., F -..õ..,-.Ø.- ,-- -,---, .. F
H2N = H2N µ1 H2N1 H2/4' 1 F N".1., F N----k1 N'''',- F
F. .A. ....:-i -N. J.. F- N J., A ---. N. CHF2 F
.F I i;I: F X
1121.1 HX µ
I
N'- F
= N I
N').õ1õ, F
F
F F F ,-- N, F
I --- F F
I I Fyll v NF
Hei- ..= H-Xkruu -' -.---------r--N"'" 0 N' i F F
O,NK-IT , ,ori j_li ,, I 1 eN
'-'0'''N
H I 3, H I 11 1 .2,r.:1( Hõ,-;11,----C. QH;;\-- F - H.:N-'201-0 N'N, 0 N., F r:Cno Nr, F
F .., N, F
,o, N / .., CHF2 I ,, 'o '11 nr-il' -',/,.',N....,0 H I F
I , , N., 1.1,-,;( \,...,,,r.
H2N.' pH
13:21-X1( 1121, Fyil. / NL
, F 2N ,!j1õ, CoHF2 I
F ' ? ).' ' -'... 112X 1L
0 NI 0 NI F 0 N \ F
U, '0-:,cy.
,-,-2,---x -r- 0-\-------,K-F ' .2N,0" .2,,, ic F
CI,N110,'---0,%11CHF2 --all 1 1 C, -'te'0:-NN -yµ 'N--' F
....'47- MH-21-,X F
:
0 W 0 0 ri 0 :õ7:). N ,11õ1, 1 , , F c , , cN 1,. I , CN
' N ijo N , NH2 NY N 1 1,r F' ..,,,,,,,, H2N,---, m, 0 N--.) = I.,.-- I
, F -0 N 1 N 0 N
, 1 m , I N
, I , H '-'1,) HIX'-7 HNN' WI
Yk 0, , N 'T'''N . oi:In. N Fis 2 In N 1 H J-,c,-- - OH I- I ;.. F 'Cr 'II- -F
H,A '(0 5 H -:-?1 The present invention further provides a pharmaceutical composition, comprising the compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to any one of the technical solutions described above, and a 10 pharmaceutically acceptable carrier and/or excipient.
Further, the pharmaceutical composition or pharmaceutical preparation comprises 1-1500 mg of the compound, or the stereoisomer, deuterated compound, solvate, pharmaceutically acceptable salt or co-crystal thereof according to any one of the preceding technical solutions, and a pharmaceutically acceptable carrier 15 and/or excipient.
The present invention further relates to the use of the compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to any one of the technical solutions described above, or the composition in the preparation of a drug for treating an 20 AAK1-mediated disease, wherein the AAK1-mediated disease is neuropathic pain, such as diabetic neuropathic pain or post-herpetic neuralgia.

The present invention further provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound, or the stereoisomer, deuterated compound, solvate, pharmaceutically acceptable salt or co-crystal thereof according to any one 5 of the preceding technical solutions, and a pharmaceutically acceptable carrier and/or excipient, wherein the therapeutically effective amount is preferably 1-mg; the disease is preferably neuropathie pain; and the disease is more preferably diabetic neuropathic pain or post-herpetic neuralgia.
The present invention further provides a method for treating a disease in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the compound, or the stereoisomer, deuterated compound, solvate, pharmaceutically acceptable salt or co-crystal thereof or the pharmaceutical composition according to the present invention. In some embodiments, the mammal according to the present invention comprises humans.
15 The term "effective amount" or "therapeutically effective amount" according to the present application refers to a sufficient amount of the compound disclosed in the present application that is administered to ameliorate, to some extent, one or more symptoms of a disease or condition being treated. In some embodiments, the outcome is the reduction and/or remission of signs, symptoms or causes of the 20 disease, or any other desired change in the biological system. For example, an "effective amount". in terms of the therapeutic use is an amount of the composition comprising the compound disclosed in the present application that is required to provide clinically significant reduction of the symptoms of the disease.
Examples of the therapeutically effective amount include, but are not limited to 1-1500 mg, 25 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-90 mg, 5-70 30 mg, 5-80 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-1500 mg, 10-1000 mg, 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg. 10-450 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-125 mg, 10-100 mg, 10-90 mg, 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg; 20-1500 mg, 20-1000 mg, 20-900 mg, 20-800 mg, 20-700 mg. 20-600 mg, 20-500 mg, 20-400 mg, 20-350 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg. 20-125 mg, 20-100 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg; 50-1500 mg, 50-1000 mg, 50-900 mg, 50-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 5 mg, 50-150 mg, 50-125 mg, 50-100 mg; 100-1500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, or 100-200 mg.
The present invention relates to a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of the compound, or the stereoisomer, deuterated compound, solvate, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, and a carrier and/or excipient. The pharmaceutical composition can be in a unit preparation form (the amount of the active drug in the unit preparation is also referred to as the "preparation specification"). In some embodiments, the 15 pharmaceutical composition comprises the compound, or the stereoisomer, deuterated compound, solvate, pharmaceutically acceptable salt, or co-crystal thereof according to the present invention in an amount including but not limited to 1-1500 mg, 5-1000 mg, 10-800 mg, 20-600 mg, 25-500 mg, 40-200 mg, 50-100 mg, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 20 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg. 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg. 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg. 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 25 750 mg, 775 mg. 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, and 1500 mg.
The present invention further provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound, or the stereoisomer, deuterated compound, 30 solvate, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, and a pharmaceutically acceptable carrier and/or excipient, wherein the therapeutically effective amount is preferably 1-1500 mg; the disease is preferably neuropathic pain; and the disease is more preferably diabetic neuropathic pain or post-herpetic neuralgia.

The present invention further provides a method for treating a disease in a mammal, the method comprising administering to a subject a drug, i.e., the compound, or the stereoisomer, deuterated compound, solvate, pharmaceutically acceptable salt or co-crystal thereof according to the present invention, and a 5 pharmaceutically acceptable carrier and/or excipient in a daily dose of 1-mg/day, wherein the daily dose can be a single dose or divided doses; in some embodiments, the daily dose includes, but is not limited to 10-1500 mg/day, 20-1500 mg/day, 25-1500 mg/day, 50-1500 mg/day, 75-1500 mg/day, 100-1500 mg/day, 200-1500 mg/day, 10-1000 mg/day, 20-1000 mg/day, 25-1000 mg/day, 50-1000 mg/day, 75-1000 mg/day, 100-1000 mg/day, 200-1000 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, or 200-400 mg/day; in some embodiments, the daily dose includes, but is not limited to 1 mg/day, 5 mg/day, 10 mg/day, 20 mg/day, mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 15 mg/day, 400 mg/day, 600 mg/day, 800 mg/day, 1000 mg/day, 1200 mg/day, mg/day, or 1500 mg/day.
The present invention relates to a kit, wherein the kit can comprise a composition in the form of a single dose or multiple doses and comprises the compound, or the stereoisomer, deuterated compound, solvate, pharmaceutically 20 acceptable salt or co-crystal thereof according to the present invention, and the amount of the compound, or the stereoisomer, deuterated compound, solvate, pharmaceutically acceptable salt or co-crystal thereof according to the present invention is identical to the amount of same in the above-mentioned pharmaceutical composition.
25 In the present invention, the amount of the compound, or the stereoisomer, deuterated compound, solvate, pharmaceutically acceptable salt or co-crystal thereof according to the present invention is calculated in the form of a free base in each case.
The term "preparation specification" refers to the weight of the active drug 30 contained in each vial, tablet or other unit preparation.
Synthetic Route Those skilled in the art would have been able to prepare the compounds of the present invention by means of combining the documents WO 2017059085, WO
2017059080, and WO 2015153720 and known organic synthesis techniques, wherein the starting materials used therein are commercially available chemicals and (or) compounds described in chemical documents. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include:
Titan Technology Co., Ltd., Energy Chemical Co.. Ltd., Shanghai Demo Co., Ltd., Chengdu Kelong Chemical Co., Ltd., Accela ChemBio Co., Ltd., PharmaBlock Sciences (Nanjing), Inc.. WuXi Apptec Co., Ltd., J&K Scientific Co., Ltd., etc.
References and monographs in the art introduce in detail the synthesis of reactants that can be used to prepare the compounds described herein, or provide articles describing the preparation method for reference. The references and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. 0. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York. 1992; J.
March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992; Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V.
"Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN
0-19-509618-5; I _,arock, R. C. "Comprehensive Organic Transformations: A
Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J.
(editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1;
Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN:
0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley &
Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley &
Sons, in 73 volumes.

Specific and similar reactants can be selectively identified by the indexes of known chemicals prepared by the Chemical Abstracts Service of the American Chemical Society, wherein the indexes are available in most public libraries or university libraries and online. Chemicals that are known but not commercially 5 available in the catalog are optionally prepared by custom chemical synthesis plants, wherein many of standard chemical supply plants (for example, those listed above) provide custom synthesis services. Reference document for the preparation and selection of the pharmaceutically acceptable salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts-, 10 Verlag Helvetica Chimica Acta, Zurich, 2002.
Term Unless otherwise specified, the terms of the present invention have the following meanings.
The carbon, hydrogen, oxygen, sulphur, nitrogen and halogen involved in the 15 groups and compounds of the present invention all comprise isotopes thereof, and are optionally further substituted with one or more of the corresponding isotopes thereof, wherein the isotopes of carbon comprise 12C, 13C and 14C; the isotopes of hydrogen comprise protium (II), deuterium (D, also known as heavy hydrogen), and tritium (T, also known as superheavy hydrogen); the isotopes of oxygen 20 comprise 160, 170 and 180; the isotopes of sulphur comprise 32, "S, 34S
and "S;
the isotopes of nitrogen comprise 14N and 15N; the isotope of fluorine comprises 19F; the isotopes of chlorine comprise 35C1 and 37C1; and the isotopes of bromine comprise 79Br and "Br.
The expression "Cx_y group" refers to a group comprising x to y carbon atoms, 25 for example, "C1_6 alkyl" refers to an alkyl group comprising 1-6 carbon atoms.
The term "halogen" refers to fluorine (F). chlorine (Cl), bromine (Br), iodine (I) or isotopes thereof.
The term "halo" or "substituted with halogen" means that the hydrogen atoms are substituted with one or more groups selected from F, Cl, Br, I, or isotopes 30 thereof, wherein the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the group to be substituted. Without particular limitation, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen, 1-3 halogen, 1-2 halogen, and 1 halogen; and when the number of halogen substituents is greater than 1, the group to be substituted can be substituted with the same or different halogen.
The term "halo C1-6 alkyl" refers to an alkyl group comprising 1-6 carbon atoms in which one or more hydrogens are substituted with one or more halogen 5 atoms (e.g., fluorine, chlorine, bromine, and iodine), wherein the upper limit of the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the alkyl group. Without particular limitation, the number of halogen substituents is any integer between 1 and the upper limit, preferably halogen, 1-3 halogen, 1-2 halogen, or 1 halogen; and when the number of halogen 10 substituents is greater than 1, the group to be substituted can be substituted with the same or different halogen. Examples include, but are not limited to -CF3, -CH/CI, -CH2CF3, -CC12, CF3, etc.
The term "deuterium" refers to the isotope deuterium of hydrogen (H).
The term "deuterated" or "deuterated compound" refers to the case where a 15 hydrogen atom on a group, such as alkyl, cycloalkyl, alkylene, aryl, heteroaryl, mercapto, heterocycloalkyl, alkenyl and alkynyl is substituted with at least one deuterium atom, wherein the upper limit of the number of deuterium substituents is equal to the sum of the number of hydrogens that can be substituted in the group to be substituted. Without particular limitation, the number of deuterium substituents 20 is any integer between 1 and the upper limit, preferably 1-20 deuterium atoms, 1-deuterium atoms, 1-6 deuterium atoms, 1-3 deuterium atoms, 1-2 deuterium atoms or 1 deuterium atom.
The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group. Unless otherwise specified, the alkyl refers to an alkyl group 25 comprising 1 to 20 carbon atoms, preferably an alkyl group comprising 1 to 8 carbon atoms, more preferably an alkyl group comprising 1 to 6 carbon atoms, further preferably an alkyl group comprising 1 to 4 carbon atoms, and further preferably an alkyl group comprising 1-2 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-30 butyl, n-pentyl, isoamyl, neopentyl, n-hexyl, etc. The alkyl can be further substituted with any substituent.
The term "hydroxyalkyl" refers to alkyl substituted with hydroxyl, wherein the alkyl is as defined above.

The term "alkenyl" refers to a straight or branched hydrocarbon group comprising at least one carbon-carbon double bond (C=C), and the main chain comprises 2 to 18 (such as 2 to 8, further such as 2 to 6, and more further such as 2 to 4) carbon atoms unless otherwise specified. Examples of alkenyl include, but are 5 not limited to vinyl, allyl, 1-propcnyl, 2-propcnyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4--pentenyl, 1-methyl-l-butenyl, 2-methy1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-l-pentenyl, 2-methyl-l-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-10 decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, etc.; and the alkenyl can be optionally further substituted with any group.
The term "alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond (CC). The main chain comprises 2 to 18 (such as 2 to 8, further such as 2 to 6, and more further such as 2 15 to 4) carbon atoms. "Alkynyl" includes but is not limited to ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methy1-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, etc. The alkynyl can be optionally further substituted with any substituent.
20 The term "alkoxy" or "alkyloxy" refers to -0-alkyl. Without particular limitation, alkoxy or alkyloxy is -0-Cis alkyl, preferably -0-C1-6 alkyl, more preferably -0-Ci_4 alkyl, and further preferably -0-C1.2 alkyl. Non-limiting examples of alkoxy or alkyloxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, secbutoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropoxy, 25 cyclobutoxy, etc. The alkoxy can be optionally further substituted with any substituent.
The term "haloalkoxy" refers to -0-haloalkyl. Without particular limitation, haloalkoxy is -0-halo CI -8 alkyl, preferably -0-halo C1_6 alkyl, more preferably -0-halo CI -4 alkyl, and further preferably -0-halo C1-2 alkyl, wherein the upper limit of 30 the number of halogen substituents is equal to the sum of the number of hydrogens that can be substituted in the group to be substituted. Without particular limitation, the number of halogen substituents is any integer between 1 and the upper limit, preferably 1-5 halogen, 1-3 halogen, 1-2 halogen, and 1 halogen; and when the number of halogen substituents is greater than 1, the group to be substituted can be substituted with the same or different halogen. Non-limiting examples of haloalkoxy include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, difluoroethyloxy, etc.
The term "cycloalkyl" refers to a substituted or unsubstituted, saturated or 5 partially unsaturated non-aromatic hydrocarbon ring. Cycloalkyl can be a monocyclic, bicyclic or polycyclic ring, wherein the bicyclic or polycyclic ring can be a fused ring, a Spiro ring or a bridged ring. Unless otherwise specified, cycloalkyl usually contains 3 to 20 carbon atoms. When cycloalkyl is monocyclic cycloalkyl, the cycloalkyl contains preferably 3-15 carbon atoms, preferably 3-10 carbon atoms, also preferably 3-8 carbon atoms, more preferably 3-6 carbon atoms, and further preferably 3-4 carbon atoms; and when cycloalkyl is bicyclic or polycyclic cycloalkyl, the cycloalkyl contains preferably 4-12 carbon atoms, preferably 4-11 carbon atoms, also preferably 5-11 carbon atoms, more preferably 6-11 carbon atoms, and further preferably 6-10 carbon atoms. Non-limiting 15 examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, /"--) cycloheptyl, butenyl, cyclopentenyl. cyclohexenyl, , 0.<1 0> Co a 17s1 , 0, etc.
The term "heterocycloalkyl" refers to a substituted or unsubstituted, saturated or partially unsaturated non-aromatic ring containing at least one heteroatom.
20 Unless otherwise specified, heterocycloalkyl is a 3- to 20-membered ring.
When heterocycloalkyl is monocyclic heterocycloalkyl, the heterocycloalkyl is preferably a 3- to 15-membered, preferably 3- to 10-membered, also preferably 3- to 8-membered, and further preferably 3- to 6-membered ring; and when heterocycloalkyl is bicyclic or polycyclic heterocycloalkyl, the heterocycloalkyl is 25 preferably a 4- to 12-membered, preferably 4- to 11-membered, also preferably 5-to 11-membered. more preferably 6- to 11-membered. and further preferably 6-to 10-membered ring. Heterocycloalkyl can be a monocyclic, bicyclic or polycyclic ring, wherein the bicyclic or polycyclic ring can be a bridged ring, a fused ring and a spiro ring, in which the heteroatoms are selected from heteroatoms N, S. 0, P and 30 Si and oxidation states thereof. When heterocycloalkyl is a bicyclic or polycyclic ring, at least one ring contains at least one heteroatom, and the heterocycloalkyl can be a bicyclic or polycyclic ring formed by a ring containing the heteroatom(s) and a ring containing no heteroatom. When heterocycloalkyl is connected to other groups, a connection point can be at a heteroatom or a carbon atom. Non-limiting examples of heterocycloalkyl include azetidinyl, morpholinyl, piperazinyl, piperidyl, tetrahydropyranyl, oxetanyl, pyranyl. azacyclopentenyl, azacyclohexcnyl, oxacyclopentcnyl, oxacyclohexcnyl, etc.
The term "aryl" refers to a substituted or unsubstituted aromatic 5- to 15-membered carbocycle, and includes monocyclic aryl and fused aryl. Aryl is preferably a 5- to 10-membered aromatic ring, and further preferably a 5- to 8-membered aromatic ring. Aryl ring can be fused to a non-aryl ring (such as a heteroaryl, heterocycloalkyl or cycloalkyl ring), wherein the aryl ring is the connection site, and non-limiting examples thereof comprise phenyl, naphthyl, anthryl, phenanthryl, 1-0N0 , 4 i4 ¨N
N ' I \ ¨N, and . N
, The aryl can be optionally further substituted with any substituent.
The term "heteroaryl ring" or "heteroaryl" refers to a substituted or unsubstituted aromatic ring containing at least one heteroatom or group selected from heteroatoms N, S, 0, P and Si and oxidation states thereof. Heteroaryl ring or heteroaryl can be a monocyclic, bicyclic or polycyclic ring, wherein the bicyclic or polycyclic ring can be a bridged ring, a fused ring and a spiro ring. Bicyclic or polycyclic heteroaryl ring or heteroaryl can be formed by fusion of heteroaryl to a non-heteroaryl ring such as cycloalkyl, heterocycloalkyl and aryl, or of heteroaryl to heteroaryl, wherein the heteroaryl ring is the connection site. Non-limiting examples of heteroaryl ring or heteroaryl include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, II
0\ NH 0 0 N
indolyl, purinyl, N

-js_12 IN;
I
, etc. The heteroaryl can be optionally further substituted with any sub stituent.
CA 03225894 2024¨ 1¨ 15 The term "carboxyl" refers to -C(=0)-0H.
"Spiro ring" refers to a 5- to 20-membered polycyclic group sharing one carbon atom (referred to as a Spiro atom) between substituted or unsubstituted rings, which may contain 0 to 5 double bonds, and may contain 0 to 5 heteroatoms 5 or groups selected from N, 0, S, P. Si and oxidation states thereof. The Spiro ring is preferably 6- to 14-membered, further preferably 6- to 12-membered, and more preferably 6- to 10-membered. The Spiro ring can be formed between cycloalkyl and heterocycloalkyl. The Spiro ring is preferably a Spiro ring formed by a three-membered ring and a three-membered ring, a three-membered ring and a four-membered ring, a three-membered ring and a five-membered ring, a three-membered ring and a six-membered ring, a four-membered ring and a four-membered ring, a four-membered ring and a five-membered ring, a four-membered ring and a six-membered ring, a five-membered ring and a five-membered ring or a five-membered ring and a six-membered ring; non-limiting examples of the Spiro 15 ring include -o)<1 X > >CO
-J
X :0 \ ______________________________________________ s \ </)0 (>0 C)%
- -A-- OC c 0(DNf H N30 H H N\ HN HN
HN
N
= (DN
HNI HN HN HN. HN
N
J
0 ' ; and the spiro ring can be optionally further substituted with any substituent.
20 A "fused ring" refers to a polycyclic group in which the rings share two adjacent atoms, wherein one or more rings may contain 0 or more double bonds, and may be substituted or unsubstituted, and each ring in the fused ring system may contain 0 to 5 heteroatoms selected from N, S, 0, P, Si and oxidation states thereof. The fused ring is preferably 5- to 20-membered, further preferably 5-to 25 14-membered, more preferably 5- to 12-membered, and still further preferably 5-to 10-membered. Preferably, the fused ring may be in the form of a three-CA 03225894 2024¨ 1¨ 15 membered ring fused a four-membered ring (indicating a fused ring formed by a three-membered ring and a four-membered ring, and either the three-membered ring or the four-membered ring may be possibly used as the basic ring according to the IUPC nomenclature; similarly hereinafter), a three-membered ring fused a five-membered ring, a three-membered ring fused a six-membered ring, a four-membered ring fused a four-membered ring, a four-membered ring fused a five-membered ring, a four-membered ring fused a six-membered ring, a five-membered ring fused a five-membered ring, a five-membered ring fused a six-membered ring, and a six-membered ring fused a six-membered ring; and non-limiting examples include purine, quinoline, isoquinoline, benzopyran, benzofuran, benzothiophene, <Do, , 0 js>. .q> c>,G E.
UL:r\jui-i (10 N N , . The fused ring can be optionally further substituted with any substituent.
A "bridged ring" refers to a ring system in which two rings share two non-adjacent atoms, which may contain 0 or more double bonds, and may be substituted or unsubstituted, wherein one or more rings may contain 0 to 5 heteroatoms selected from N, S, 0, P, Si and oxidation states thereof. The ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to atoms, and still further preferably 5 to 10 atoms; and non-limiting examples include adamantane, G!7' \

HNI 0 HN¨

Qd_ 11 0 NH HN HN
, NH NH , HN3 HNa HNC] HNO
HNO HN\S7 HNNH
H N H HN HN-.\NH ID
, =

The heteroatom according to the present invention can be selected from N, 0, S, Si, P atoms and oxidation states thereof.
The term "optional" or "optionally" refers to that the events or circumstances subsequently described may but not necessarily occur, and the description includes 5 the occasions where the events or circumstances occur or do not occur.
For example, "alkyl optionally substituted with F" means that the alkyl may but not necessarily be substituted by F, and the description includes the case where the alkyl is substituted with F and the case where the alkyl is not substituted with F.
Unless otherwise specified, substitution with a substituent described herein 10 refers to substitution at a position allowed by chemical theory, and the number of substituents conforms to the rules of chemical bonding.
The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which salt maintains the biological effectiveness and characteristics of a free acid or a free base and is obtained by reacting the free acid 15 with a non-toxic inorganic base or organic base, or reacting the free base with a non-toxic inorganic acid or organic acid.
The term "pharmaceutical composition" represents a mixture of one or more compounds described herein or the stereoisomers, solvates, pharmaceutically acceptable salts, co-crystals or deuterated compounds thereof and other 20 components comprising physiologically/pharmaceutically acceptable carriers and/or exeipients.
The term "carrier" refers to: a system that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound, and can change the way the drug enters the human 25 body and the distribution of the drug in the body, control the release rate of the drug and delivery the drug to targeted organs. Non-limiting examples of the carrier include microcapsule, microsphere, nanoparticle, liposome, etc.
The term "excipient" refers to: a substance that is not a therapeutic agent per se, but used as a diluent, adjuvant, adhesive and/or vehicle for addition to a 30 pharmaceutical composition, thereby improving the disposal or storage properties thereof, or allowing to or promoting the formation of a compound or a pharmaceutical composition into a unit dosage form for administration. As is known to those skilled in the art, a pharmaceutically acceptable excipient can provide various functions and can be described as a wetting agent, a buffer, a suspending agent, a lubricant, an emulsifier, a disintegrating agent, an absorbent, a preservative, a surfactant, a colorant, a flavouring agent and a sweetening agent.
Examples of pharmaceutically acceptable excipients include, but are not limited to:
(1) sugars, such as lactose, glucose and sucrose; (2) starch, such as corn starch and 5 potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and croscarmellose (such as croscarmellose sodium); (4) tragacanth powder; (5) malt; (6) gelatine; (7) talc; (8) excipients, such as cocoa butter or suppository wax; (9) oils, such as peanut oil, 10 cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) diols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate;
(13) agar; (14) buffers, such as magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
15 (19) ethanol; (20) pH buffered solution; (21) polyester, polycarbonate and/or polyanhydride; and (22) other non-toxic compatible substances used in a pharmaceutical preparation.
The term "stereoisomer" refers to an isomer produced as a result of different spatial arrangement of atoms in molecules, including cis-trans isomers, 20 en anti omers and conformational isomers.
The term "solvate" refers to a substance formed by the compound of the present invention or the salt thereof and a stoichiometric or non-stoichiometric solvent bound by intermolecular non-covalent forces. When the solvent is water, the solvate is a hydrate.
25 The term "co-crystal" refers to a crystal formed by the combination of active pharmaceutical ingredient (API) and co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure state of API and CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between various components. The co-crystal is a multi-component crystal, which includes 30 both a binary co-crystal formed between two neutral solids and a multi-element co-crystal formed between a neutral solid and a salt or solvate.
Brief Description of the Drawings Figure 1 shows the time-MPT curve of the experiment with the SNL-induced mouse model of neuropathic pain.
Detailed Description of Embodiments 5 The technical solutions of the present invention will be described in detail below in conjunction with the drawings and examples, but the scope of protection of the present invention includes but is not limited thereto.
The content of the present invention is described in detail with the following examples. If a specific condition is not indicated in the examples, a conventional 10 condition is used in an experimental method. The listed examples are intended to better illustrate the content of the present invention, but should not be construed as limiting the content of the present invention. According to the above-mentioned content of the invention, those skilled in the art can make unsubstantial modifications and adjustments to the embodiments, which still fall within the 15 protection scope of the present invention.
Test method The structures of the compounds are determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (6) is given in the unit of 10-6 (ppm). NMR is measured with (Bruker Avance III 400 and Bruker 20 Avance 300) NMR instrument, and the solvent for determination is deuterated dimethyl sulphoxide (DMSO-d6), deuterated chloroform (CDC13), deuterated methanol (CD30D), and the internal standard is tetramethylsilane (TMS);
MS is determined with Agilent 6120B (ESI) and Agilent 6120B (APCI):
HPLC is determined with Agilent 1260DAD high pressure liquid 25 chromatograph (Zorbax SB-C18 100 x 4.6 mm, 3.5 M);
Yantai Huanghai HSGF254 or Qingdao 0F254 silica gel plate is used as a thin layer chromatography silica plate, and the silica gel plate for the thin layer chromatography (TLC) is of the specification of 0.15 mm-0.20 mm, and the specification when separating and purifying a product by thin layer 30 chromatography is 0.4 mm - 0.5 mm.
and for the column chromatography, Yantai Huanghai silica gel of 200-300 mesh silica gel is generally used as a carrier.
Description of abbreviations:
TI-IF: Tetrahydrofuran CbzCl: Benzyl chloroformate NaOH: Sodium hydroxide KOAc: Potassium acetate DAST: Diethylaminosulphur trifluoride 5 Xphos: 2-di cycl ohexylpho sphin o-2',4',6'-tri i s opropylbi phenyl Xphos PdG2: C hl oro(2-di cycl oh exylpho sphin o-2',4',6'-tri i sopropy1-1,1'-bipheny1)[2-(2'-amino-1,1'-bipheny1)1palladium (II) Intermediate 1: 6-bromo-2-(difluoromethyl)-3-fluoropyridine (immediate 1) Br N CHO Br I F
Step 1 10 1A Intermediate 1 Step 1: 6-bromo-2-(difluoromethyl)-3-fluoropyridine (immediate 1) Raw material 1A (10 g, 49 mmol) was dissolved in 200 mL of dichloromethane, and the mixture was cooled to -20 C. DAST (11.7 mL, 88 mmol) was added and the resulting mixture was slowly warmed to room temperature and 15 reacted for 5 h. Upon complete depletion of raw materials monitored by TLC, the reaction was quenched with saturated aqueous sodium bicarbonate solution. The resulting reaction mixture was extracted with ethyl acetate and the organic phase was subjected to rotary evaporation. Then the residue was purified by silica gel column (petroleum ether : ethyl acetate = 20 : 1) to obtain the target compound 20 intermediate 1 (9.8 g, 89%).
11-1 NMR (400 MHz, CDCb) 67.65 ¨ 7.58 (m, 1H). 7.46 ¨ 7.40 (m, 1H), 6.85 ¨ 6.56 (m, 1H).
Intermediate 2: (2-(difluoromethyppyridin-4-yl)boronic acid (immediate 2) N
Br _______________________________________________ F
Step 1 -==='-'B(01-1) 2 25 2A Intermediate 2 Step 1: (2-(difluoromethyppyridin-4-yeboronic acid (immediate 2) 2A (5g. 24 mmol), Xphos PdG2 (189 mg, 0.24 mmol, CAS: 1310584-14-5), Xphos (229 mg, 0.48 mmol, CAS 564483-18-7), bis(pinacolato)diboron (9.14 g, 36 mmol) and KOAc (7.07 g, 72 mmol) were added to a flask. After nitrogen replacement, 200 mL of ethanol was added and the mixture was heated to 80 C
and reacted for 5 h. Upon complete depletion of raw materials monitored by TLC, water was added to quench the reaction. The system was subjected to rotary evaporation to remove ethanol and then extracted with ethyl acetate. The organic 5 phase was subjected to rotary evaporation to obtain intermediate 2 (5.1 g).
LC-MS (EST): mlz = 174.1 [M+Hr.
Intermediate 3: (S)-2-amino-2,4-dimethylpent-4-en-1-ol R
0 o q, Chiral _________________________________________ 0 0-2S.NH µINICbz preparation cy'Sµ,0 ' , Step! Step 2 c Step 3 9 0 9,0 -\s'?
0 0-s L ,Ncbz , ____ Step 4 Step 5 H2N
3F 3G Intermediate 3 Step 1: 4-methy1-514-1,2,3-oxathiazole 2,2-dioxide (3C) 10 Under nitrogen atmosphere, chlorosulphonyl isocyanate (62 mL) was added to a three-necked round bottom flask, then 200 mL of dichloromethane was added, and the system was cooled to 0 C. 27 mL of formic acid was dissolved in 50 mL
of dichloromethane. The mixture was slowly added to the system while the temperature was controlled at 0 C. After 30 minutes, the mixture was warmed to 15 room temperature and stirred overnight. Hydroxyacetone (36.3 mL) and pyridine (58 mL) were dissolved in 1000 mL of dichloromethane. At 0 C, the mixture was slowly added dropwise to the system. After the addition was completed, the system was warmed to room temperature and stirred overnight. The system was subjected to rotary evaporation to remove the organic solvent and the residue was purified by 20 silica gel column (eluent: dichloromethane) to obtain the title compound 3C (36 g, 56%).
111 NMR (400 MHz, CDC13) 6 5.06 (s, 2H), 2.42 (s, 3H).
Step 2: 4-methyl-4-(2-methylally1)-1,2,3-oxathiazoli dine 2,2-dioxide (3D) Under nitrogen atmosphere, 3C (36 g, 267 mmol) was dissolved in 800 mL of 25 methyl tert-butyl ether. The system was cooled to 0 C and then a solution of 2-methylallylmagnesium chloride in tetrahydrofuran (0.55 L, 0.5 M) was added dropwise. Upon complete depletion of raw materials monitored by TLC, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate and then subjected to rotary evaporation. The residue was purified by silica gel column to obtain the title compound 3D (43 g, 84%).
1H NMR (400 MHz, CDC13) 6 5.06 ¨ 5.01 (m, 1H), 4.85 ¨ 4.83 (m, 1H), 4.59 (s, 11-1), 4.38 (d, 11-1), 4.27 (d, 1H), 2.57 ¨ 2.50 (m, 1H). 2.42 ¨ 2.29 (m, 114), 1.84 5 (s, 31-1), 1.46 (s, 31-1).
Step 3: Benzyl 4-methy1-4-(2-methylally1)-1,2,3-oxathiazolidine-3-carboxyl ate 2,2-di oxi de (3E) Under nitrogen, 3D (1.91 g, 10 mmol) was dissolved in 50 mL of tetrahydrofuran. A solution of 1 M potassium tert-butoxide in tetrahydrofuran (15 10 mL) was added, followed by CbzCl (2.1 mL, 15 mmol). Upon complete depletion of raw materials monitored by TLC, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution. The system was subjected to rotary evaporation to remove tetrahydrofuran, extracted with ethyl acetate, and then subjected to rotary evaporation. The residue was then purified by silica gel 15 column (petroleum ether : ethyl acetate = 10 : 1) to obtain the title compound 3E
(2.6 g, 80%).
LC-MS (EST): m/z = 343.0 [M+NI-14r.
120 g of 3E was subjected to chiral preparation to obtain the target compound 3F (55 g).
20 Preparation method: instrument: Waters SFC 150 Mgm, column: DAICEL
CHIRALPAK OJ (250 mm x 50 mm, 10 lam); mobile phase: A for CO2 and B for Me0H (BASE); gradient: 10% B; flow rate: 130 mL/min, back pressure: 100 bar;
column temperature: 35 C; wavelength: 220 nm; cycle time: 4.5 min; sample preparation: sample concentration: 157.5 mg/ml, ethanol solution; sample 25 injection: 0.8 ml/injection. After separation, the fractions were dried on a rotary evaporator at the bath temperature of 40 C to obtain compound 3F (retention time:
0.680 minutes).
Step 4: (S)-4-methy1-4-(2-methylally1)-1,2,3-oxathiazolidine 2,2-dioxide (3G) Compound 3F (5 g, 15.4 mmol) was dissolved in 500 mL of methanol and 50 30 mg of 10% palladium on carbon catalyst was added. The mixture was subjected to hydrogen replacement. Upon the disappearing of fluorescence monitored by TLC, the system was filtered by suction to remove palladium on carbon from the system.
The resulting filtrate was subjected to rotary evaporation to obtain the title compound 3G (crude), which was directly used in the next step.

Step 5: (S)-2-amino-2,4-dimethylpent-4-en-1-ol (intermediate 3) Compound 3G was dissolved in 150 mL of tetrahydrofuran. At 0 C, lithium aluminium hydride (1.8 g, 47.4 mmol) was added in portions and the mixture was warmed to room temperature and stiffed overnight. Water (1.8 mL), 10% aqueous sodium hydroxide solution (3.6 mL) and water (5.4 mL) were added and the mixture was stirred for 1 h. The resulting reaction mixture was filtered by suction to remove the solid. The resulting filtrate was subjected to rotary evaporation to obtain intermediate 3 (crude product), which was directly used in the next reaction.
LC-MS (EST): m/z = 130.1 [M+Hr.
Intermediate 4: (2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (intermediate 4) ja Br H2N --- Step 1 631,)Br , Step 2 !a Step 3 313, Br 0 N
B(OH) 2 4A 4B ac Intermediate Step 1: 2-amino-4-bromopyri dine 1-oxide (4B) Compound 4A (10 g, 57.8 mmol) was dissolved in 200 mL of acetone. At room temperature, m-chloroperoxybenzoic acid (11 g, 63.6 mmol) was dissolved in 200 mL of acetone and then the resulting mixture was added. The reaction mixture was stirred for 5 min to produce a large quantity of a solid. The solid was collected by suction filtration, washed with acetone, and dried to obtain compound 4B (crude product, 10.7 g, 98%).
LC-MS (EST): m/z = 189.0 and 191.0 [M+Hr.
Step 2: Methyl (4-bromopyridin-2-yl)carbamate (4C) Compound 4B (crude, 10.7 g) was dissolved in trimethyl orthoformate (200 mL) and 1.25 mL of boron trifluoride diethyl etherate was added. The system was heated to 105 C and reacted overnight. The system was subjected to rotary evaporation to remove the organic phase and then separated by column chromatography to obtain compound 4C (9.1 g, 69%).
LC-MS (ESI): m/z = 231.0 and 233.0 [M+Hr.
Step 3: (2-((methoxycarbonyl)amino)pyridin-4-yl)boronic acid (intermediate 4) Compound 4C (3.5 g, 15.1 mmol), Xphos PdG2 (600 mg, 0.76 mmol, CAS:
1310584-14-5), Xphos (700 mg, 1.47 mmol, CAS 564483-18-7), potassium acetate (4.5 g, 45.8 mmol) and bis(pinacolato)diboron (6 g, 23.6 mmol) were dissolved in 250 mL of ethanol in a round bottom flask. The system was subjected to nitrogen replacement, warmed to 80 C and reacted overnight. The system was subjected to rotary evaporation to remove ethanol and then extracted with ethyl acetate to 5 obtain the title compound intermediate 4 (4 g).
LC-MS (EST): m/z = 197.1 [M+Hr.
Intermediate 5: 5-bromo-3-(difluoromethyl)-2-fluoropyridine Step 1 N F
5A Intermediate 5 Step 1: 5-bromo-3-(difluoromethyl)-2-fluoropyridine (intermediate 5) 10 Raw material 5A (5.00 g, 24.51 mmol) was dissolved in 100 mL of dichloromethane, and the mixture was cooled to -20 C. DAST (6.5 mL, 49.02 mmol) was added, and the resulting mixture was slowly warmed to room temperature and reacted for 2 h. Upon complete depletion of raw materials monitored by TLC, the reaction was quenched with saturated aqueous sodium 15 bicarbonate solution and extracted with dichloromethane. The organic phase was subjected to rotary evaporation and the residue was purified by silica gel column (petroleum ether : ethyl acetate = 20 : 1) to obtain intermediate 5 (5.00 g, 90.27%).
11-1 NMR (400 MHz, CDC13) 8.40 (dd, 1H), 8.15 (dt, 1H), 6.95 ¨ 6.67 (m, 20 1H).
Example 1 142',5-bis(difluoromethyl)-[3,4'-bipyridin]-6-yeoxy)-4-fluoro-2,4-dimethylpentan-2-amine (compound 1) -S

Ho Intermediate 1 F
Intermediate 2 "--Xy Step 1 H2N Step 2 Step 3D lb lc :=\
N
N
N
F F
Step 4 F F Step 5 ld le N I N
c<OH Step 6 F

if Compound 1 Step 1: 2-amino-2,4-dimethylpent-4-en-1-ol (lb) 3D (8 g, 42 mmol) was dissolved in 500 mL of tetrahydrofuran. The system was cooled to 0 C and lithium aluminium hydride (3.99 g, 105 mmol) was slowly 5 added. Then the mixture was warmed to room temperature and reacted for 6 h.
Water (4 mL), 8 M aqueous NaOH solution, and water (12 mL) were sequentially added and the mixture was stirred for 1 h. The resulting mixture was filtered by suction to remove the solid and the resulting filtrate was subjected to rotary evaporation to obtain the target compound lb (crude product, 9 g), which was 10 directly used in the next step without purification.
LC-MS (ESI): mh = 130.2 [M+Hr.
Step 2: 1-((6-bromo-2-(difluoromethyppyridin-3-ypoxy)-2,4-dimethylpent-4-en-2-amine (lc) Crude product lb (2 g) was added to a solution of potassium tert-butoxide in 15 tetrahydrofuran (27 mL). At room temperature, the mixture was stirred for 5 min and then intermediate 1 (4 g, 18 mmol) was added. The resulting mixture was subjected to nitrogen replacement, then heated to 80 C and reacted overnight.
The system was subjected to rotary evaporation to remove the organic phase, and the residue was separated and purified by silica gel column chromatography 20 (dichloromethane : methanol = 10 : 1) to obtain the target compound lc(1.1 g, 35%).
LC-MS (EST): m/z = 335.1 and 337.1 [M+Hr.
Step 3: 1-((2',6-bi s(difluoromethy1)42,4'-bipyri din1-5-yeoxy)-2,4-dimethylpent-4-en-2-amine (1d) Intermediate 2(1.1 g, 3.3 mmol), 1 c (880 mg, 5 mmol), potassium phosphate (9.2 g, 43 mmol), Xphos PdG2 (500 mg, 0.63 mmol, CAS: 1310584-14-5), and Xphos (650 mg, 1.36 mmol, CAS 564483-18-7) were added to a sealed tube, and 30 mL of tetrahydrofuran was added. After nitrogen replacement, the mixture was 5 warmed to 80 C and reacted for 5 h. Upon complete depletion of raw materials monitored by TLC, the system was filtered by suction to remove the solid, which was then washed with methanol. The filtrate was collected and subjected to rotary evaporation, and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol = 10 : 1) to obtain the title 10 compound id (360 mg, 29%).
LC-MS (ESI): m/z = 384.2 [M+1-11+.
111 NMR (400 MHz, DMSO-d6) 6 8.80¨ 8.76 (m, 1H), 8.42 ¨ 8.36 (m, 1H), 8.32 (s, 1H), 8.24¨ 8.18 (m, 1H), 7.84 ¨ 7.79 (m, 1H), 7.42¨ 6.88 (m, 2H), 4.87 (s, 11-1), 4.72 (s, 114), 3.88 (s, 211), 2.22 (s, 211), 1.78 (s, 31-1), 1.15 (s, 311).
15 Step 4: 4-amino-5-((2',6-bis(difluoromethyl)-[2,41-bipyridin1-5-yl)oxy)-4-methylpentan-2-one (le) id (360 mg, 0.94 mmol) was dissolved in 20 mL of dichloromethane. The mixture was cooled to -60 C and ozone was introduced. Upon complete depletion of raw materials monitored by TLC, 1 g of triphenylphosphine was added and the 20 system was warmed to room temperature and stiffed for 15 min. The organic phase was subjected to rotary evaporation and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol = 10: 1) to obtain the title compound le (300 mg, 83%).
LC-MS (ESI): m/z = 386.2 [M+Hr.
25 Step 5: 4-amino-54(2',6-bis(difluoromethy1)42,4'-bipyridin1-5-ypoxy)-2,4-dimethylpentan-2-ol (11) Under nitrogen atmosphere, le (300 mg, 0.78 mmol) was dissolved in 20 mL
of tetrahydrofuran and the system was cooled to 0 C. A solution of methylmagnesium bromide in THF (1 mL, 3 M) was added and the mixture was 30 slowly warmed to room temperature. Upon complete depletion of raw materials monitored by TLC, the reaction was quenched by the addition of saturated aqueous ammonium chloride solution, and extracted with dichloromethane. The organic phase was subjected to rotary evaporation to obtain the title compound if (240 mg, 0.6 mmol), which was directly used in the next step.

LC-MS (EST): m/z = 402.2 [M+Hr.
Step 6: 1-((2',6-bi s(di fluoromethy1)42,4'-bipyri din] -5-yl)oxy)-4-fluoro-2,4-dimethylpentan-2-amine (compound 1) Under nitrogen atmosphere, if (240 mg, 0.6 mmol) was dissolved in 15 mL of 5 dichloromethane and the mixture was cooled to -78 C. DAST (0.4 mL, 2.8 mmol) was added and the system was slowly warmed to room temperature. Upon complete depletion of raw materials monitored by TLC, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was subjected to rotary evaporation and 10 then the resulting product was separated by HPLC and lyophilized to obtain the title compound 1 (110 mg, 42%).
LC-MS (ESI): m/z = 404.2 [M+Hr.
11-1 NMR (400 MHz, DMSO-d6) 6 8.82 ¨ 8.76 (m, 1H), 8.42 ¨ 8.36 (m, 1H), 8.32 (s, 111), 8.23 ¨ 8.18 (m, 114), 7.81 ¨7.75 (m, 1I-1), 7.41 ¨6.89 (m, 214), 3.95 15 (s, 2H), 1.94 ¨ 1.86 (m, 2H), 1.49 ¨ 1.36 (m, 6H), 1.23 (s, 3H).
Example 2 1421,6-bis(difluoromethy1)42,4'-bipyridinl-5-yeoxy)-2-methyl-3-(1-methylcyclopropyl) propan-2-amine (compound 2) 9 o o OH
j() ___________________________ NLy\!121c7 Step 1 Step 2 Step 3 Step 3E 2b 2c 2d N
Br Step 5 ' 2e Compound 2 20 Step 1: Benzyl 4-methyl-44(1-methylcyclopropyl)methyl)- 1 ,2,3-oxathi azoli dine-3-carboxylate 2,2-dioxide (2b) Under nitrogen, diethylzinc (12 mL, 2 M toluene solution) was added to a three-necked flask and 50 mL of dichloromethane was added. The system was cooled to 0 C. Trifluoroacetic acid (1.8 mL, 24 mmol) was added. Upon complete 25 gas evolution, diiodomethane (2 mL, 24 mmol) was added and the mixture was stirred at 0 C for 20 min. 3E (2.6 g, 8 mmol) was added and the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water and then extracted with dichloromethane. The organic phase was subjected to rotary evaporation to obtain the title compound 2h (1.57 g, 58%).

LC-MS (EST): m/z = 357.11M+NH4r.
Step 2: 4-methyl-4-(( 1-m ethyl cycl opropyl)m ethyl)- 1,2,3-oxathi az oli dine 2,2-5 dioxide (2c) 2b (1.57 g, 4.63 mmol) was dissolved in 50 mL of methanol and 400 mg of 10% Pd/C was added. Under hydrogen atmosphere, the mixture was heated to 60 C and reacted overnight. Upon complete depletion of raw materials, the system was filtered by suction to remove palladium on carbon. The filtrate was collected 10 and subjected to rotary evaporation to obtain the title compound 2c (929 mg, 97%).
Step 3: 2-amino-2-methyl-3-(1-methylcyclopropyl)propan-l-ol (2d) 2c (929 mg, 4.5 mmol) was dissolved in 50 mL of tetrahydrofuran and at 0 C, lithium aluminium hydride (600 mg, 15.8 mmol) was added. The mixture was warmed to room temperature and stirred overnight. Water (0.6 mL), 10% aqueous 15 sodium hydroxide solution (1.2 mL) and water (1.8 mL) were sequentially added.
The mixture was stirred for 30 min and then filtered by suction to remove the solid.
The resulting filtrate was subjected to rotary evaporation to obtain a crude containing the target compound 2d (close to 1 g), which was directly used in the next step without further purification.
20 LC-MS (EST): m/z = 144.2[M+H]t Step 4: 1-((6-bromo-2-(di fluorom ethypp yri di n-3-yl)oxy)-2-m ethyl-3-(1-methylcyclopropyl)propan-2- amine (2e) The crude containing 2d ( 1 g) and a solution of 1 M potassium tert-butoxide in THF (15 mL) were stirred at room temperature for 5 min and intermediate 1 25 (1.13 g, 5 mmol) was added. After nitrogen replacement, the mixture was warmed to 80 C and stirred overnight. After the reaction was completed, the system was subjected to rotary evaporation and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol = 10 : 1) to obtain title compound 2e (600 mg, 2-step total yield: 37%).
30 LC-MS (ESI): m/z = 349.1 and 351.1[M+Hr.
Step 5: 1-((2',6-bi s (di fluoromethyl)- [2,4'-bi pyri di n] -5-yl)oxy)-2-m ethy1-3-( 1-methylcyclopropyl) propan-2-amine (compound 2) 2e (600 mg, 1.7 mmol), intermediate 2 (500 mg, 2.84 mmol), potassium phosphate (5.2 g, 24.3 mmol), Xphos PdG2 (280 mg, 0.35 mmol, CAS: 1310584-14-5), and Xphos (364 mg, 0.76 mmol, CAS 564483-18-7) were added to a sealed tube, and 20 mL of tetrahydrofuran was added. After nitrogen replacement, the mixture was warmed to 80 C and reacted for 5 h. Upon complete depletion of raw materials monitored by TLC, the system was filtered by suction to remove the 5 solid, which was then washed with methanol. The filtrate was collected and subjected to rotary evaporation and the residue was separated and purified by silica gel column chromatography (dichloromethane : methanol = 10: 1) and preparative HPLC and lyophilized to obtain title compound 2 (117 mg, 17%).
LC-MS (EST): m/z = 398.2 [M+H].
10 111 NMR (400 MHz, DMSO-d6) 8 8.80 ¨ 8.76 (m, 1H), 8.42 ¨ 8.36 (m, 1H), 8.32 (s, 111), 8.23 ¨ 8.18 (m, 114), 7.83 ¨ 7.78 (m, 11-1), 7.37 ¨ 6.87 (m, 2I4), 3.93 (s, 21-1), 1.63 ¨ 1.49 (m, 3H), 1.44 ¨ 1.37 (m, 1H), 1.19 (s, 3H), 1.14 (s, 3H), 0.36 ¨
0.14 (m, 4H).
Examples 3 and 4 15 (S)-1-42',6-bis(difluoromethy1)42,42-bipyridin1-5-yl)oxy)-2,4-dimethylpent-4-en-2-amine and (R)-14(2',6-bis(difluoromethy1)42,4'-bipyridin1-5-yl)oxy)-2,4-dimethylpent-4-en-2-amine (compound 3 and compound 4) FNF
N
F Chiral preparation H2N
F
N F N F
Compound 3 and H2N compound 1d id (80 mg) was subjected to chiral resolution to obtain compound 3 (33.7 mg) 20 and compound 4 (25.3 mg).
Preparation method:
instrument: SHIMADZU LC-20AP, column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 pm); mobile phase: A: n-hexane, B: ethanol (0.1% NI-13.1120);
gradient: 8% B gradient elution; flow rate: 120 mL/min, column temperature:
25 25 C, wavelength: 254 nm, cycle time: 16 min; sample preparation: sample concentration: 1.5 mg/ml, ethanol solution; sample injection: 2 ml/injection.
After separation, the fractions were dried on a rotary evaporator at the bath temperature of 40 C to obtain P1 (retention time: 2.658 minutes, set to be compound 3) and (retention time: 4.205 minutes, set to be compound 4).

Example 5 (S)-N-(4-(44(2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-3-cyanophenyppyridin-2-yl)acetamide (compound 5) 0 o Br CN Br 401 CN 0 AN I
CN
Intermediate 3 5c 44r F Step I y H2 N Step 2 5a 5b Compound 5 5 Step 1: (S)-242-amino-2,4-dimethylpent-4-en-1-yl)oxy)-5-bromobenzonitrile (5b) Intermediate 3 (0.5 g, 3.87 mmol) and raw material 5a (1.17 g, 5.80 mmol) were dissolved in 10 ml of anhydrous tetrahydrofuran and then a solution of 1 M
potassium tert-butoxide in tetrahydrofuran (4.64 ml, 4.64 mmol) was added. The 10 mixture was heated to 70 C and reacted for 16 h. Upon complete depletion of raw materials monitored by TLC, the reaction mixture was concentrated and the residue was purified by column chromatography (dichloromethane : methanol = 20 : 1) to obtain the target compound 5b (0.8 g, 67%).
LC-MS (EST): mlz = 311.1 [M+Hr.
15 Step 2: (S)-N-(4-(442-amino-2,4-dimethylpent-4-en- 1 -yl)oxy)-3-cyanophenyl) pyridin-2-yl)acetamide (compound 5) Raw material 5b (0.7 g, 2.26 mmol), 5c (0.81 g, 4.52 mmol, prepared with reference to WO 2010038465), and anhydrous potassium carbonate (0.94 g, 6.78 mmol) were dissolved in dioxane (10 ml) and water (2 m1). Under nitrogen 20 protection, X-PhosPd G 2 (0.18 g, 0.23 mmol) was added and the mixture was heated to 90 C and reacted for 6 h. When the reaction was complete as shown by LC-MS, the reaction mixture was concentrated and the residue was purified by silica gel column (dichloromethane : methanol = 10: 1) to obtain crude compound 5, which was then separated and purified by silica gel column chromatography 25 (acetonitrile : water = 40 : 60) to obtain compound 5 (130 mg, 15.63%).
LC-MS (EST): mlz = 365.3 [M+H].
111 NMR (400 MHz, DMSO-d6) 6 10.55 (s, 1H), 8.39 ¨ 8.31 (m, 2H), 8.12 (d, 11-1), 7.99 (dd, 11-1), 7.43 (dd, 111), 7.38 (d, 1H), 4.86 (dd, 11-1), 4.71 (s, 11-1), 3.89 (s, 2H), 2.23 (s, 2H), 2.12 (s, 3H), 1.79 (s, 3H), 1.15 (s, 3H).
30 Example 6 (S)-N-(4-(442-amino-4-fluoro-2,4-dimethylpentyl)oxy)-3-eyanophenyl)pyridin-2-yl)acetamide (compound 6) AN CN AN
CN
Step 1 Compound 5 Compound Step 1: (S)-N-(4-(4-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-3-5 cyanophenyl) pyridin-2-yl)acetami de (compound 6) Ferric nitrate nonahydrate (0.44 g, 1.08 mmol) was dissolved in water (10 me. The mixture was ultra-sonicated for 5 min and cooled to 0 C. Then a solution of selective fluorination reagent (0.38 g, Mol: 1.08 mmol) in 5 ml of acetonitrile was added, followed by a solution of compound 5 (100 mg, 0.27 mmol) in 5 ml of 10 acetonitrile. Sodium borohydride (0.13 g, 3.51 mmol) was then added in portions.
The mixture was reacted for 2 h. When the reaction of the raw materials was completed as shown by LC-MS, the reaction mixture was purified by column chromatography (acetonitrile : water = 40 : 60) to obtain compound 6 (90 mg, 87.60%).
15 LC-MS (EST): ink = 385.0[M+H].
11-1 NMR (400 MHz, DMSO-d6) 6 10.56 (s, 1H), 8.39 ¨8.31 (m, 21-1), 8.19 (s, 111), 8.12 (d, 114), 8.00 (dd, 1H), 7.43 (dd, 11-1), 7.37 (d, 111), 4.04 ¨
3.94 (m, 211), 2.12 (s, 3H), 1.96 (s, 1H), 1.91 (d, 1H), 1.47 (d, 3H), 1.42 (d, 3H), 1.27 (s, 3H).
Examples 7 and 8 20 M ethyl- (S)-(5- ((2-ami no-2,4-di m ethylpent-4-en-1 -yl)oxy)-4 - (tri fluoromethyl) -[2,4'-bipyridin]-2'-yl)carbamate and methyl- (R)-(5-((2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-4-(trifluoromethyl)- [2,4'-bipyri din] -2'-yl)carbamate (compound 7 and compound 8) o Br CFq CF
- Step 1 Br ,CF3 Step 2 N 3 rN) F
I-12N H24 \
7a 7b 7c 0 N o Chiral resolution `-0)-N CF3 3+CF
-0"
N.

Compound 7, compound 8 Step 1: 14(6-bromo-4-(trifluoromethyppyridin-3-ypoxy)-2,4-dimethylpent-4-en-2-amine (7b) Compound 7a (1 g, 4.1 mmol), compound lb (1 g, 0.4 mmol) and 15 mL of potassium tert-butoxide (1 M in TI-IF) were added to a sealed tube. After nitrogen replacement, the system was warmed to 80 C and reacted for 3 h. The reaction mixture was subjected to rotary evaporation and the residue was mixed with silica gel and separated by column chromatography to obtain the target compound 7b (1 g, 69%).
LC-MS (EST): m/z = 353.1 and 355.1[M+H].
Step 2: Methyl -(54(2-amino-2,4-dimethylpent-4-en-1 -ypoxy)-4-(trifluoromethyl)-[2,4'-bipyridin1-2'-y1)carbamate (7c) Intermediate 4 (1 g, 2.8 mmol), 7b (1 g, 3.6 mmol), Xphos PdG2 (400 mg, 0.5 mmol, CAS: 1310584-14-5), Xphos (500 mg, 1.05 mmol, CAS 564483-18-7), and potassium phosphate (9 g, 42.4 mmol) were added to a sealed tube, and 20 mL
of tetrahydrofuran was added. After nitrogen replacement, the system was warmed to 80 C and reacted for 3 h. The resulting reaction mixture was mixed with silica gel, separated by column chromatography and preparative HPLC, and then lyophilized to obtain compound 7c (100 mg, 9%).
LC-MS (EST): m/z = 425.2 [M+Hr.
111 NMR (400 MHz, DMSO-d6) 6 10.25 (s, 8.81 (s, 11-1), 8.53 (s, 1H), 8.38 - 8.34 (m, 1H). 8.17 (s, 1H), 7.75 - 7.71 (m, 114), 4.86 (s, 1H), 4.69 (s, 1H), 4.04 (s, 2H), 3.71 (s, 3H), 2.20 (s, 2H), 1.78 (s, 3H), 1.13 (s, 3H).
7c (90 mg) was subjected to chiral resolution to obtain compound 7 (29.7 mg) and compound 8 (31.0 mg).
Preparation method: instrument: Waters 150 AP, column: DAICEL
CHIRALCEL AD (250 mm x 30 mm, 10 lam); mobile phase: (phase A: CO2, phase B: Et0H (0.1% NH3=H20)); gradient: 50% mobile phase B isocratic elution;

flow rate: 80 mL/min, back pressure: 100 bar, column temperature: 35 C;
wavelength: 220 nm; cycle time: 9.2 min; sample preparation: sample concentration: 5 mg/ml, acetonitrile solution; sample injection: 2 ml/injection.
After separation, the fractions were dried on a rotary evaporator at the bath temperature of 40 C to obtain P1 (retention time: 0.846 minutes, set to be compound 7) and P2 (retention time: 1.441 minutes, set to be compound 8).
Example 9 Methyl (S)- (5-((2-amino-2,4-dimethylpent-4-en- 1-yl)oxy)-6-(difluoromethyl)- [2,4'-bipyri di n1-2'-y1) carbamate (compound 9) Bli Step 1 ,c)Krsi r\ Step 2 I N, F
F Intennediate 4 H I F Intermediate 3 I
F121\1' =
Intermediate 1 9a Compound g Step 1: Methyl (6-(di fluorom ethyl )-5-fluoro-pyri di n]-2'-yl)carb amate 5 (9a) Intermediate 4 (500 mg, 1.8 mmol), intermediate 1 (500 mg, 2.2 mmol), Xphos PdG2 (200 mg, 0.25 mmol, CAS: 1310584-14-5), Xphos (250 mg, 0.52 mmol, CAS 564483-18-7), and potassium phosphate (4.5 g, 21.2 mmol) were added to a sealed tube, and 20 mL of tetrahydrofuran was added. After nitrogen 10 replacement, the system was warmed to 80 C and reacted for 3 h. The resulting reaction mixture was mixed with silica gel and separated by column chromatography to obtain compound 9a (197 mg, 37%).
LC-MS (EST): m/z = 298.1 [M+Hr.
Step 2: Methyl (S)-(54(2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-6-15 (di fluorom ethyl)- [2,4'-bipyri di n] carb am ate (compound 9) Compound 9a (197 mg, 0.66 mmol), intermediate 3 (90 mg, 0.7 mmol) and 1 mL of potassium tert-butoxide (1 M in TI-IF) were added to a sealed tube.
After nitrogen replacement, the system was warmed to 80 C and reacted for 3 h. The reaction solution was concentrated to dryness and the residue was purified by 20 preparative separation to obtain the target compound 9 (30 mg, 11%).
LC-MS (EST): m/z = 407.1 [M+Hr.
11-1 NMR (400 MHz, DMSO-d6) 6 10.23 (s, 1H), 8.49 (s, 1H), 8.38 ¨ 8.33 (m, 11-1), 8.18 ¨8.13 (m, 1H). 7.79 ¨ 7.75 (m, 11-1), 7.69 ¨ 7.63 (m, 11-1), 7.40 ¨ 7.08 (m, 11-1), 4.86 (s, 11-1), 4.71 (s, 1H), 3.88 (s, 2H), 3.71 (s. 31-1), 2.23 (s, 21-1), 1.78 (s, 25 3H), 1.14 (s, 3H).
Example 10 Methyl (S)-(5-((2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-6-methyl- [2,4'-bipyridin1-2'-yl)carbamate (compound 10) Br 0 N"
Step I
= Step 2 0 N
II N

y F
Intermediate 4 N
F Intermediate 3 -0 10a 10b Compound 10 Step 1: Methyl (5-fluoro-6-methyl-[2,4'-bipyridin]-2'-yl)carbamate (10b) 10a (1.5 g, 7.89 mmol), intermediate 4 (2.3 g. 11.84 mmol), potassium phosphate (21.8 g, 102.57 mmol), Xphos PdG2 (1.24 g, 1.58 mmol, CAS:
5 1310584-14-5), and Xphos (1.5 g, 3.16 mmol, CAS 564483-18-7) were added to a sealed tube, and 60 mL of tetrahydrofuran was added. After nitrogen replacement, the mixture was warmed to 80 C and reacted for 5 h. Upon complete depletion of raw materials monitored by TLC, the system was filtered by suction to remove the solid, which was then washed with methanol. The filtrate was collected and 10 subjected to rotary evaporation and the residue was purified by silica gel column (dichloromethane : methanol = 10 : 1) to obtain the title compound 10b (1.4 g, 68%).
LC-MS (ESI): m/z = 262.0 [M+Hr.
Step 2: Methyl (S )-(5((2-ami no-2,4-di methylpent-4-en-l-yl)oxy)-6-m ethyl-15 [2,4'-bipyridin1-2'-yl)carbamate (compound 10) Intermediate 3 (495 mg, 3.83 mmol) was added to 15 mL of DMF solution.
Under an icc bath, Nall (275 mg, 11.49 mmol) was added and the mixture was stirred for 10 min. Then compound 10b (1 g, 3.83 mmol) was added. After nitrogen replacement, the mixture was reacted at 0 C for 1 h. The reaction was 20 quenched by the addition of water and the mixture was then extracted with ethyl acetate. The organic phase was subjected to rotary evaporation and the residue was purified by column chromatography (dichloromethane : methanol = 10 : 1) to obtain compound 10 (110 mg).
LC-MS (ESI): m/z = 371.2 [M+Hr.
25 11-1 NMR (400 MHz, DMSO-d6) 6 10.16 (s, 1H), 8.47 (s, 1H), 8.29 (d, 1H), 7.80 (d, 11-1), 7.62 (dd, 11-1), 7.40 (d, 11-1), 4.86 (s, 11-1), 4.70 (s, 11-1), 3.75 (s, 214), 3.70 (s, 3H), 2.50 (s, 3H), 2.23 (s, 2H), 1.78 (s, 3H), 1.58 (s, 2H), 1.14 (s, 3H).
Example H
Methyl (S)-(5-((2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-4-(di fluoro-13-30 methyl)-[2,4'-bipyri din1-2'-yecarb am ate (compound 11) o N 0 N
Br CF2 1 I
I\Ta Step I CF2 Step 2 1 CF2 F Intermediate 4 h N Intermediate 3 N

ha lib Compound ii Step 1: Methyl (4-(difluoro-13-methyl)-5-fluoro-[2,4'-bipyridin1-2'-yl)carbamate (11b) ha (1.0 g, 4.42 mmol), intermediate 4 (1.3 g, 6.64 mmol), potassium 5 phosphate (12.2 g, 57.52 mmol), Xphos PdG2 (0.7 g, 0.88 mmol, CAS:

14-5), and Xphos (0.85 g, 1.77 mmol, CAS 564483-18-7) were added to a sealed tube, and 30 mL of tetrahydrofuran was added. After nitrogen replacement, the mixture was warmed to 80 C and reacted for 5 h. Upon complete depletion of raw materials monitored by TLC, the system was filtered by suction to remove the 10 solid, which was then washed with methanol. The filtrate was collected and subjected to rotary evaporation and the residue was purified by silica gel column (dichloromethane : methanol = 10: 1) to obtain the title compound lib (600 mg, 46%).
LC-MS (EST): m/z = 298.0 [M+Hr.
15 Step 2: Methyl (S)-(5-((2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-4-(difluoro-13-methyl)-[2,4'-bipyri din1-2'-yl)carbamate (compound 11) Intermediate 3 (260 mg, 2.02 mmol) was added to a solution of potassium tert-butoxide in tetrahydrofuran (3 mL) and the mixture was stirred at room temperature for 5 min. A solution of compound lib (600 mg, 2.03 mmol) in 20 tetrahydrofuran (6 mL) was added. After nitrogen replacement, the mixture was heated to 80 C and reacted overnight. The system was subjected to rotary evaporation to remove the organic phase and the residue was purified by column chromatography (dichloromethane : methanol = 10 : 1) to obtain compound 11(20 mg).
25 LC-MS (EST): m/z = 407.1 [M Hr.
1H NMR (400 MHz, DMSO-d6) 6 10.24 (s, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 8.35 (d, 1H), 8.07 (s. 1H), 7.69 (dd, 1H), 7.48 ¨ 7.21 (m, 1H), 4.86 (s, IH), 4.71 (s, 1H), 3.99 (s, 2H), 3.71 (s, 3H), 2.22 (s, 2H), 1.79 (s, 3H), 1.13 (s, 3H).
Example 12 30 (S)-4-amino-5((2',6-bi s (di fluoromethy1)42,4'-bipyri din1-5-yl)oxy)-2,4-dimethylpentan-2-ol (compound 12) F
Step 1 Br F Step 2 F F

Intermediate 3 Intermediate 1 12a 12b Step 3 F F Step 4 F

12c Compound 12 Step 1: (S)-14(6-bromo-2-(difluoromethyl)pyridin-3-yl)oxy)-2,4-dimethylpent-4-en-2-amine (12a) Intermediate 3 (1 g, 7.7 mmol), intermediate 1 (1.6 g, 7.1 mmol) and 12 mL
5 of potassium tert-butoxide (1 M in TI-IF) were added to a sealed tube.
After nitrogen replacement, the system was warmed to 80 C and reacted for 3 h. The system was cooled to room temperature, mixed with silica gel, and separated by column chromatography (petroleum ether: ethyl acetate = 1 : 1 to ethyl acetate ) to obtain the target compound 12a (500 mg, 21%).
10 LC-MS (EST): m/z = 355.1 [M+Hr.
Step 2: (S)-142',6-bis(difluoromethyl)42,4'-bipyridinl-5-y1)oxy)-2,4-dimethylpent-4-en-2-amine (12b) Compound 12a (500 mg, 1.5 mmol), intermediate 2 (620 mg, 3.6 mmol), Xphos PdG2 (200 mg, 0.25 mmol, CAS: 1310584-14-5), Xphos (250 mg, 0.52 15 mmol, CAS 564483-18-7), and potassium phosphate (4.5 g, 21.2 mmol) were added to a sealed tube, and 20 mL of tetrahydrofuran was added. After nitrogen replacement, the system was warmed to 80 C and reacted for 3 h. The resulting reaction mixture was mixed with silica gel and separated by column chromatography (petroleum ether : ethyl acetate = 1 : 1 to ethyl acetate) to obtain 20 compound 12b (350 mg. 61%).
LC-MS (EST): m/z 384.2 [M+Hr.
Step 3: (S)-4-ami no-5-((2',6-bi s(difluoromethy1)42,4'-bipyri di n1-5-yl)oxy)-methylpentan-2-one (12c) Compound 12b (350 mg, 0.91 mmol) was dissolved in 20 mL of 25 dichloromethane. The system was cooled to -78 C and ozone was introduced.
Upon complete depletion of raw materials monitored by TLC, excess triphenylphosphine was added and the mixture was slowly warmed to room temperature, mixed with silica gel, and separated by column chromatography (petroleum ether : ethyl acetate = 1 : 1 to ethyl acetate) to obtain compound 12c (310 mg, 89%).
LC-MS (EST): m/z = 386.1 [M+Hr.
Step 4: (S)-4-amino-5-((2',6-bi s(difluorom ethyl)-12,4'-bipyri din1-5-yl)oxy)-5 2,4-dimethylpentan-2-ol (compound 12) Compound 12c (160 mg, 0.42 mmol) was dissolved in 10 mL of tetrahydrofuran and the mixture was subjected to nitrogen replacement. At 0 C, 1.4 mL of methylmagnesium chloride (3 M, dissolved in THF) was added. The mixture was slowly warmed to room temperature, and the reaction was quenched 10 by the addition of saturated aqueous ammonium chloride solution. The system was subjected to rotary evaporation to remove the organic phase, extracted with dichloromethane and then subjected to rotary evaporation. The residue was purified by preparative separation and then lyophilized to obtain compound 12 (30 mg, 18%).
15 LC-MS (EST): m/z = 402.2 [M+Hr.
11-1 NMR (400 MHz, DMSO-d6) 6 8.81 - 8.78 (m, 1H), 8.42 - 8.37 (m, 1H), 8.32 (s, 11-1), 8.23 - 8.19 (m, 11-1), 7.81 - 7.74 (m, 11-1), 7.41 - 6.88 (m, 21-1), 4.02 -3.91 (m, 21-1), 1.71 (d, 11-1), 1.60 (d, 1H), 1.27 (s, 31-1), 1.23 (s, 31-1), 1.16 (s, 31-1).
Example 13 20 (S)-N-(4-(4-((2-ami no-2,4-dim ethylpent-4-en-l-yl)o xy)-3-(triflu orom ethyl) phenyl)pyridin-2-yl)acetamide (compound 13) 0 !la H2N = HO( )L11 Br fah CF, 5c ) 9 :C., eF
Intermediate 3 )N111CF3---F Step 1 H Step 2 (37')-r H2N =
13a 13b Compound 13 Step 1: Tut-butyl N-(4-(4-fluoro-3-(trifluoromethyl)phenyl)pyridin-2-yl)acetamide (13b) 25 13a (1.5 g, 6.17 mmol), 5c (1.93 g, 7.40 mmol), Pd3(dba)2 (485.0 mg, 0.617 mmol), X-Phos (588.6 mg, 1.23 mmol), and K3PO4 (13.0 g, 61.7 mmol) were sequentially added to a single-necked flask and then THF (40 mL) was added.
The system was subjected to nitrogen replacement 3 times and reacted at 80 C for 4 hours. After the reaction was completed, THF was removed by rotary evaporation.
30 Water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL) twice. The organic phases were combined and dried over anhydrous sodium sulphate, and the solvent was removed. The residue was then separated by column chromatography (petroleum ether : ethyl acetate (v/v) = 2 : 1) to obtain the title compound 13b as a white solid (1.45 g, 78.8%).
LC-MS (EST): m/z = 299.1 [M+Hr.
5 Step 2: (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-3-(trifluorom ethyl) ph enyl)pyri di n-2-yl)ac etami de (compound 13) Intermediate 3 (300.0 mg, 2.32 mmol) was added to a sealed tube and then TI-IF (20 mL) was added. Subsequently, 13b (831.6 mg, 2.79 mmol) and potassium tert-butoxide (781.3 mg, 6.97 mmol) were sequentially added and the mixture was purged with nitrogen for 2 minutes and reacted at 80 C for 4 hours. After the reaction was completed, TI-IF was removed by rotary evaporation. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL) twice. The organic phases were combined and dried over anhydrous sodium sulphate, and the solvent was removed. The residue was then separated by column chromatography 15 (dichloromethane : methanol (v/v) = 20 : 1) to obtain the title compound 13 (300 mg, 31.7%).
11-1 NMR (400 MHz, CDCb) 6 8.43 (s, 1H), 8.29 (d, 1H), 8.17 (s, 1H), 7.88 (d, 11-1), 7.81 (dd, 11-1), 7.22 (dd, 11-1), 7.05 (d, 1H), 4.97-4.93 (m, 11-1), 4.79-4.77 (m, 1H), 3.85 (q, 2H), 2.38-2.30 (m, 2H), 2.24 (s, 3H). 1.82 (s, 3H). 1.27 (s, 3H).
20 LC-MS (EST): m/z = 408.2 [M+Hr.
Example 14 (S)-N-(4-(442-amino-4-fluoro-2,4-dimethylpentypoxy)-3-(trifluoromethyl) phenyl)pyridin-2-yl)acetamide (compound 14) it I
CF3 it I

H
H2N Step 1 Compound 13 Compound 14 25 Step 1: (S)-N-(4-(44(2-amino-4-fluoro-2,4-dimethylpentypoxy)-3-(trifluoromethypphenyepyridin-2-y1)acetamide (compound 14) Ferric nitrate nonahydrate (1.20 g, 2.95 mmol) was dissolved in water (15 mL). The mixture was ultra-sonicated for 5 min and then acetonitrile (15 mL) was added. The mixture was cooled to 0 C and subjected to nitrogen replacement 3 30 times. Then a selective fluorination reagent (1.04 g, 2.95 mmol) was added, followed by a solution of compound 13 (300 mg, 0.74 mmol) in 5 mL of acetonitrile. Sodium borohydride (365.0 mg, 9.58 mmol) was added in portions.
The mixture was reacted for 2 h. When the reaction of the raw materials was completed as shown by LC-MS, ammonia water (2 mL) was added to quench the reaction, followed by extraction with DCM twice. The organic phases were 5 combined and dried over anhydrous sodium sulphate and the solvent was removed.
The residue was separated by column chromatography (dichloromethane :
methanol = 20: 1) to obtain compound 14 (200 mg, 63.5%).
11-1 NMR (400 MHz, CDC13) 6 8.43 (s, 1H), 8.29 (d, 11-1), 8.09 (s, 114), 7.87 (d, 1H), 7.81 (dd, 1H), 7.22 (dd, 11-1), 7.07 (d, 1H), 4.00-3.96 (m, 2H), 2.24 (s, 10 3H), 2.02 (dd, 2H), 1.51 (d, 3H), 1.45 (d, 3H), 1.38 (s, 3H).
LC-MS (EST): mh = 428.2 [M+Hr.
Example 15 (S)-N-(5-((2-amino-2,4-dimethylpent-4-en-l-yeoxy)-6-(difluoromethyl)-[2,41-bipyridin1-21-yl)acetamide (compound 15) BrNF 0 5c 0 N
I k Intermediate 3 H
Step 1' Step 2 15 Intermediate 1 ma Compound 15 Step 1: N-(6-(difluoromethyl)-5-fluoro- [2.4'-bipyri din] -2'-yl)acetami de (15a) 5c (900 mg), intermediate 1 (633 mg, 2.8 mmol), Xphos PdG2 (250 mg, 0.32 mmol), Xphos (500 mg, 1.05 mmol), and potassium phosphate (6.0 g, 28.3 mmol) were added to a sealed tube, and 30 mL of tetrahydrofuran was added. After 20 nitrogen replacement, the system was warmed to 80 C and reacted for 3 h.
The resulting reaction mixture was mixed with silica gel and separated by column chromatography to obtain compound 15a (428 mg, 54%).
LC-MS (EST): m/z = 282.2 [M+H].
Step 2:
(S)-N-(5-((2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-6-25 (difluorom ethyl) - [2,4'-bipyridin]-2'-yl)acetamide (compound 15) Compound 15a (200 mg, 0.71 mmol), intermediate 3 (100 mg, 0.77 mmol) and 2.5 mL of potassium tcrt-butoxide (1 M in TI-IF) were added to a sealed tube.
After nitrogen replacement, the system was warmed to 80 C and reacted for 3 h.

The reaction mixture was purified by preparative separation to obtain compound 30 15 (89 mg, 32%).
LC-MS (EST): m/z = 391.1 [M H].

- 71 -11-1 NMR (400 MHz, DMSO-d6) 6 10.54 (s, IH), 8.68 (s, 1H), 8.41 - 8.37 (m, 1H), 8.16- 8.10 (m, 1H), 7.81 -7.75 (m, 1H), 7.72 - 7.67 (m, 1H), 7.38 -7.07(m, IH), 4.86 (s, IH), 4.71 (s, IH), 3.88 (s, 2H), 2.23 (s, 2H), 2.12 (s, 3H), 1.78 (s, 3H), 1.14 (s, 31-1).
5 Example 16 (S)-N-(54(2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-6-(difluoromethyl)-[2,4'-bipyri di n1-2'-y1 )acetami de (compound 16) )LNNIF Step 1 Compound 15 Compound 16 Step 1: (S)-N-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-6-10 (difluoromethyl) -[2,4'-bipyridin1-2'-yl)acetamide (compound 16) Ferric nitrate nonahydrate (133 mg, 0.33 mmol) was dissolved in water (3 mL) and the mixture was subjected to nitrogen replacement and then cooled to 0 C. Selective fluorination reagent (117 mg, 0.33 mmol) and 3 mL of acetonitrile were added. Compound 15 (35 mg, 0.09 mmol) was dissolved in 3 mL of 15 acetonitrile and the resulting mixture was added to the system. The mixture was stirred for 5 min and then sodium borohydride (40 mg, 1.05 mmol) was added in portions. The resulting mixture was reacted for 30 min while the temperature was maintained at 0 C. Ammonia water (1 mL) was added to quench the reaction, followed by extraction with the mixed solvents of dichloromethane and methanol 20 (10: 1). After rotary evaporation, the residue was purified by preparative HPLC to obtain compound 16 (10 mg, 28%).
LC-MS (EST): m/z = 411.3 [M+Hr.
11-1 NMR (400 MHz, DMSO-d6) 6 10.55 (s, 1H), 8.69 (s, 11-1), 8.43- 8.35 (m, 1H), 8.18 - 8.10 (m, 1H). 7.78 - 7.73 (m, 11-1), 7.72 - 7.65 (m, 1H), 7.40 -7.05 25 (m, 1H), 3.94 (s, 2H), 2.12 (s, 3H), 1.95- 1.86 (m, 2H), 1.50- 1.36 (m, 6H), 1.23 (s, 31-1).
Example 17 (S)-methyl-(6-((2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-5-(difluoromethyl)-[3,4'-bipyridin1-2'-yl)carbamate (compound 17) cHF2 ,CHF2 I CHF2 I Step 1 11 I Step 2 1N 1 ThtF Intermediate 4 N F Intermediate 3 Intermediate 5 17a Compound 17 Step 1: Methyl (5-(difluoromethyl)-6-fluoro-13,4'-bipyridinl-2'-y1)carbamate (17a) Intermediate 5 (2.00 g, 8.85 mmol), intermediate 4 (2.08 g, 10.62 mmol), 5 Xphos PdG2 (1.40 g, 1.78 mmol, CAS: 1310584-14-5), Xphos (1.70 g, 3.56 mmol, CAS 564483-18-7), and potassium phosphate (22.00 g, 103.77 mmol) were added to a sealed tube, and 100 mL of tetrahydrofuran was added. After nitrogen replacement, the system was warmed to 80 C and reacted for 16 h. The resulting reaction mixture was mixed with silica gel and separated by column 10 chromatography to obtain compound 17a (2.30 g, 87.44%).
LC-MS (ESI): m/z = 298.1 [M+Hr.
Step 2: Methyl (S)-(6-((2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-5-(di fluorom ethyl)- 113,4'-bipyri di n] -2'-yl)carb am ate (compound 17) Compound 17a (2.30 g, 7.74 nimol), intermediate 3 (840 mg, 6.50 mmol) 15 and 20 mL of potassium tert-butoxide (1 M in THF) were added to a sealed tube.
After nitrogen replacement, the system was warmed to 80 C and reacted for 16 h.
The reaction mixture was mixed with silica gel and separated by column chromatography to obtain a crude, which was purified by preparative separation to obtain the target compound 17 (190 mg, 7.31%).
20 LC-MS (EST): m/z = 407.1 [M+H]t 111 NMR (400 MHz, DMSO-d6) 6 10.29 (s, 1H), 8.69 (s, 1H), 8.35 (d, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.44 (dd, 1H), 7.41 ¨ 7.14 (m, 11-1), 4.85 (s, 1I-I), 4.71 (s, 114), 4.13 (s, 214), 3.71 (s, 314), 2.22 (s, 214), 1.79 (s, 31-1), 1.12 (s, 314).
Example 18 25 (S)-m ethyl-(6-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-5- (di fl uoromethyl) - [3,41-bipyridin1-21-yl)carbamate (compound 18) -CHF2 Step I cHF, Compound 17 Compound 18 Ferric nitrate (680 mg, 1.67 mmol) was dissolved in water (5 mL). The mixture was ultra-sonicated for 5 min and cooled to 0 C. Then a solution of selective fluorination reagent (590 mg, 1.67 mmol) in 5 mL of acetonitrile was added, followed by a solution of compound 17 (170 mg, 0.42 mmol) in 5 mL of 5 acetonitrile. Sodium borohydride (210 mg, 5.45 mmol) was then added in portions.
The mixture was reacted for 1 h. When the reaction of the raw materials was completed as shown by LC-MS, the reaction mixture was diluted by the addition of water and then extracted with dichloromethane. The organic phases were combined, dried and concentrated to obtain a crude, which was purified by 10 preparative separation to obtain the target compound 18 (80 mg, 44.85%).
LC-MS (EST): m/z = 427.2[M+11]+.
111 NMR (400 MHz, CD30D) ô 8.63 (s, 1H), 8.30 (d, 1H), 8.22 (s, 1H), 8.15 (d, 1H), 7.34 (dd, 1H), 7.22 ¨ 6.94 (m, 1H), 4.38 (s, 2H), 3.80 (s, 3H), 2.05¨
2.04 (m, 11-I), 2.00-1.99 (m, 1H), 1.49 (s, 31-1), 1.43 (s, 31-1), 1.35 (s, 3H).
15 Example 19 Methyl (S)-(5-((2-amino-4-fluoro-2,4-dimethylpentyl)oxy)-6-(difluoromethyl) -[2,41-bipyridin1-21-yecarbamate (compound 19) Step 1 .1. .1 Compound 9 Compound 19 Step 1: Methyl (S)-(54(2-amino-4-fluoro-2,4-dimethylpentypoxy)-6-20 (difluoromethyl)-[2,4'-bipyridinl-2'-yl)carbamate (compound 19) Ferric nitrate nonahydrate (324 mg, 0.8 mmol) was dissolved in water (7 mL) and the mixture was subjected to nitrogen replacement and then cooled to 0 C.
Selective fluorination reagent (284 mg, 0.8 mmol) and 7 mL of acetonitrile were added and compound 9 (81 mg, 0.2 mmol) was dissolved in 7 mL of acetonitrile.
25 The resulting mixture was added to the system. The resulting mixture was stirred for 5 min and then sodium borohydride (100 mg, 2.6 mmol) was added in portions.
The reaction mixture was reacted for 30 min while the temperature was maintained at 0 C. Ammonia water (2.5 mL) was added to quench the reaction, followed by extraction with the mixed solvents of dichloromethane : methanol (10 : 1).
After 30 rotary evaporation, the residue was purified by preparative HPLC to obtain compound 19 (9 mg, 11%).

LC-MS (EST): mlz = 427.2 [M+Hr.
IHNMR (400 MHz, DMSO-d5) ö 10.25 (s, 1H), 8.49 (s, 1H), 8.38 ¨ 8.33 (m, 1H), 8.19 ¨ 8.13 (m, 1H). 7.78 ¨ 7.72 (m, 1H), 7.68 ¨7.64 (m, 1H), 7.38 ¨ 7.09 (m, 1H), 3.94 (s, 2H), 3.71 (s, 3H), 1.95¨ 1.86 (m, 2H), 1.50¨ 1.37 (m, 6H), 1.23 5 (s, 311).
Example 20 Methyl (S)-(54(2-amino-4-fluoro-24-dimethylpentyl)oxy)-4-(difluorom ethyl) -[2,4'-bipyridin1-2'-yl)earbamate (compound 20) 0),N I CHF2 Step 1 ,J1.

Compound 11 Compound 20 10 Ferric nitrate nonahydrate (180 mg, 0.44 mmol) was dissolved in water (3 mL). The mixture was ultra-sonicated for 5 min and cooled to 0 C. Then a solution of selective fluorination reagent (157 mg, 0.44 mmol) in 3 mL of acetonitrile was added, followed by a solution of compound 11(45 mg, 0.11 mmol) in 3 mL of acetonitrile. Sodium borohydride (55 mg, 1.44 mmol) was then added in portions.
15 The mixture was reacted for 1 h. When the reaction of the raw materials was completed as shown by LC-MS, the reaction mixture was diluted by the addition of water and then extracted with dichloromethane. The organic phases were combined, dried and concentrated to obtain a crude, which was purified by preparative separation to obtain compound 20 (2.4 mg, 5%).
20 LC-MS (ESI): ink = 427.2[M+H].
114 NMR (400 MHz, CD30D) 8.58 (s, 1H), 8.49 (s, 1H), 8.33 (d, 1H), 8.06 (s, 1H), 7.66 (d, 1H), 7.31 ¨ 7.04 (m, 1H), 4.17 (s, 2H), 3.80 (s, 3H), 2.07 (d, 1H), 2.02 (d, 1H), 1.50 (s, 3H), 1.44 (s, 3H), 1.38 (s, 3H).
Example 21 25 Methyl (S)-(54(2-amino-4-fluoro-2,4-dimethylpentypoxy)-6-methyl-[2,4'-bipyridin1-2'-y1) carbamate (compound 21) o 0 Step 1 Compound 10 Compound 21 Ferric nitrate nonahydrate (88 mg, 0.22 mmol) was dissolved in water (2 mL).
The mixture was ultra-sonicated for 5 min and cooled to 0 C. Then a solution of selective fluorination reagent (76 mg, 0.22 mmol) in 2 mL of acetonitrile was added, followed by a solution of compound 10 (20 mg, 0.05 mmol) in 2 mL of 5 acetonitrile. Sodium borohydride (30 mg, 0.79 mmol) was then added in portions.
The mixture was reacted for 1 h. When the reaction of the raw materials was completed as shown by LC-MS, the reaction mixture was diluted by the addition of water and then extracted with dichloromethane. The organic phases were combined, dried and concentrated to obtain a crude, which was purified by 10 preparative separation to obtain compound 21 (10 mg, 47%).
LC-MS (EST): ni/z = 391.3[M+H]t IFT NMR (400 MHz, CD30D) c5 8.42 (s, 1H), 8.27 (d, 1H), 7.76 (d, 1H), 7.61 (d, 1H), 7.40 (d, 1H), 3.98 (s, 2H), 3.80 (s, 3H), 2.57 (s, 3H), 2.09 (s, 1H), 2.04 (s, 11-1), 1.50 (d, 1.45 (d, 3H), 1.40 (s, 3H).
15 Example 22 1-(((2',6-bi s(difluoromethy1)42,4'-bipyridin1-5-yfloxy)methyl)cyclopentan-1-amine (compound 22) N F
Step 1 22a Compound 22 NH2 Step 1: 1-(((2',6-bi s(di fluoromethyl)-[2,4'-bipyridin1-5-yl)oxy)methyl) 20 cyclopentan-l-amine (compound 22) Compound 22a (50 mg, 0.15 mmol, synthesized with reference to WO
2017059085), 1-amino-1 -hydroxymethylcyclopentane (26 mg, 0.22 mmol) and potassium tert-butoxide (50 mg, 0.45 mmol) were dissolved in THF (5 mL). The mixture was reacted at 70 C for 10 hours. When the reaction was complete as 25 shown by LC-MS, the reaction mixture was concentrated and the residue was separated by column chromatography (dichloromethane : methanol = 20 : 1) to obtain compound 22 (20 mg, 36%).
LC-MS (EST): ni/z = 370.3 [M+Hr.
IR NMR (400 MHz, DMSO-d6) 6 8.81-8.46 (m, 1H). 8.34 (s, 114), 8.24 (d, 30 1H), 8.16 (s, 2H), 7.89 (d, 1H), 7.51 (t, 1H), 7.05 (t, 1H), 4.25 (s, 2H), 2.08¨ 1.55 (m, 8H).

Example 23 (S)-5-(2-acetamidopyridin-4-y1)-24(2-amino-2,4-dimethylpent-4-en-l-yl)oxy)benzamide (compound 23) AN CN
Step 1 AN NH2 Compound 5 Compound 23 5 Step 1: (S)-5-(2-acetamidopyridin-4-y1)-2-((2-amino-2,4-dimethylpent-4-en-1-yl)oxy)benzamide (compound 23) Compound 5 (100 mg, 0.27 mmol), potassium carbonate (110 mg, 0.81 mmol), 37% hydrogen peroxide (50 mg, 0.54 mmol), and dimethyl sulphoxide (21 mg, 0.27 mmol) were dissolved in methanol (5 mL) and the mixture was reacted at room temperature for 3 hours and then purified by C-18 reverse phase column chromatography (acetonitrile : water = 40 : 60) to obtain compound 23 (50 mg, 48%).
LC-MS (ESI): ink = 383.51M+Hr.
111 NMR (400 MHz, DMSO-do) (510.52 (s, 1H), 8.37 (s, 1H), 8.33-8.10 (m, 15 2H), 8.04 (s, 1H), 7.83 (d, 1H), 7.67 (s, 1H), 7.38 -7.26 (m, 2H), 4.87 (s, 1H), 4.72 (s, 1H), 3.90 (s, 2H), 2.21 (d, 2H), 2.12 (s, 3H), 1.79 (s, 3H), 1.14 (s, 3H).
Example 24 (S)-N-(4-(4-((2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-3-cyanophenyl) pyri din-2-y1)-3,3-difluorocyclobutane-l-carbox ami de (compound 24) Step 1 F
Step 2 F>0)L),I3_0H Step 3 H2N Br Br OH
4A 24a 24b CN
H2N i"
20 Compound 24 Step 1: N-(4-bromopyridin-2-y1)-3.3-difluorocyclobutane-l-carboxamide (24a) 3,3-difluorocyclobutane-1 -carboxylic acid (790 mg, 5.78 mmol) was dissolved in diehloromethane (10 mL). Oxalyl chloride (810 mg. 6.36 mmol) was diluted with dichloromethane (10 mL) and the mixture was slowly added dropwise to the reaction solution. The reaction mixture was reacted for 2 hours, concentrated, then diluted with dichloromethane (10 mL) and added dropwise to a solution of compound 4A (1 g, 5.78 mmol) and triethylamine (0.88 g, 8.67 mmol) 5 in dichloromethane (10 mL). The resulting mixture was reacted at room temperature for 2 hours. washed with saturated aqueous sodium bicarbonate solution and then water, dried over anhydrous sodium sulphate and concentrated to obtain compound 24a (1.2 g, 74%).
LC-MS (ESI): mlz = 292.1[M+H].
10 Step 2: (243,3 -difluorocycl obutan e-l-carb ox ami do)pyri di n-4-yl)b oroni c acid (24b) Compound 24a (2 g, 7.2 mmol), bis(pinacolato)diboron (2.2 g. 8.6 mmol) and potassium acetate (14 g, 14 mmol) were dissolved in 1,4-dioxane (50 mL). Under nitrogen protection, 1,1'-bi s(diphenylphosphino)ferrocene palladium dichloride (II) 15 (0.5 g, 0.72 mmol) was added. Under nitrogen protection, the reaction mixture was heated to 100 C and reacted for 16 hours. When the reaction was complete as shown by LC-MS, the reaction mixture was concentrated. Water was then added and a solid was precipitated out and filtered off to obtain an aqueous phase, which was concentrated to obtain crude compound 24b (3 g).
20 LC-MS (ESI): mlz = 257.1[M+H]t Step 3: (S)-N-(4-(442-amino-2,4-dimethylpent-4-en-l-yl)oxy)-3-cyanophenyl) pyri din-2-y1)-3,3-difluorocyclobutane-l-carboxami de (compound 24) Compound 5b (200 mg, 0.64 mmol), compound 24b (16 mg, 0.64 mmol) and potassium carbonate (88 mg, 0.64 mmol) were dissolved in water (2 mL) and 1,4-25 dioxane (10 mL). Under nitrogen protection, Xphos PdG2 (50 mg, 0.064 mmol) was then added. Under nitrogen protection, the mixture was heated to 80 C, reacted for 5 hours and concentrated. The residue was purified by column chromatography (DCM : Me0H = 10: 1) to obtain a crude, which was purified by C-18 reverse phase column chromatography (acetonitrile : water = 30 : 70) to 30 obtain compound 24 (110 mg, 39%).
LC-MS (ESI): = 441.5 [M+Hr.
1H NMR (400 MHz, DMSO-d6) 6 10.79 (s, 1H), 8.40 (d, 2H), 8.21-8.15 (m, 3H), 8.08 (d, 114), 7.49 (d, 214), 5.04 (s, 114), 4.91 (s, 11-1), 4.28-4.17 (m, 21-1), 3.33 ¨3.22 (m, 1H), 2.86 ¨ 2.75 (m, 4H), 2.62 (d, 1H), 2.43 (d, 1H), 1.81 (s, 3H), 1.40 (s, 3H).
Example 25 (1R,2R)-N-(4-(4-(((S)-2-amino-2,4-dimethylpent-4-en-1-yl)oxy)-3-5 cyan oph enyl)pyri din-2-y1)-2-fluorocyclopropan e- 1-carbo xami de (compound 25) Step 1 Step 2 . _________________________________________________________________ 2,a I
B_OH
H2N Br 4A 25b 25c 5b I
'N, CN
Step 3 Compound 25 H2N
Step 1: (1R,2R)-N-(4-bromopyridin-2-y1)-2-fluorocyclopropane-l-carboxamide (25b) (1R,2R)-2-fluoro-clopropanecarboxylic acid (3.00 g, 28.82 mmol) was added to dichloromethane (40 mL) and after nitrogen replacement, N,N-dimethylformamide (1 mL) was added. Oxalyl chloride (4.02 g, 31.70 mmol) was diluted with dichloromethane (5 mL). At room temperature, the diluted solution of oxalyl chloride in dichloromethane was slowly added dropwise to the reaction solution, and after the addition was completed, the mixture was stirred at room 15 temperature overnight. After the reaction was complete, the reaction solution was concentrated to dryness and anhydrous dichloromethane (10 mL) was added to prepare standby reaction solution 1. Raw material 4A was dissolved in dichloromethane (40 mL) and pyridine (3.42 g, 43.23 mmol) was added. Under nitrogen protection, the mixture was stirred for 15 min and then standby reaction 20 solution 1 was slowly added dropwise while the temperature was controlled at 10 C-20 C. After the addition was completed, the resulting mixture was stirred for 1 hour. After the reaction was complete, water (50 mL) was added and the mixture was washed with saturated sodium bicarbonate (50 mL). The aqueous phase was extracted with dichloromethane (50 mL). The organic layers were combined, dried 25 over anhydrous sodium sulphate and filtered. The filtrate was subjected to rotary evaporation and the residue was purified by silica gel column (petroleum ether :
ethyl acetate (v/v) = 99: 1-2: 1) to obtain the title compound 25b (5.20 g, 69%).
LC-MS (EST): m/z = 261.0 [M+Hr.

Step 2: (2-((lR,2R)-2-fluorocycloprop an e- 1-carboxamido)pyri din-4-yl)boronic acid (25c) 25b (1.00 g, 3.86 mmol), KOAc (1.14 g, 11.58 mmol) and bis(pinacolato)diboron (1.47 g, 5.79 mmol) were sequentially added to a mixed 5 solution of dioxanc (50 mL) and water (10 mL). After nitrogen replacement, [1,1'-bis(diphenylphosphino)fen-ocenelpalladium dichloride (II) (0.14 g, 0.19 mmol) was added. After additional nitrogen replacement, the mixture was reacted for hours while the temperature was maintained at 80 C. The reaction process was monitored with LC-MS. After the reaction was complete, the reaction mixture was 10 cooled to room temperature and filtered. The filtrate was concentrated to dryness.
Water (200 mL) was added and the resulting mixture was ultra-sonicated for 15 min and then filtered. The filtrate was concentrated to dryness. Dioxane (200 mL) was added and the resulting mixture was ultra-sonicated for 15 min and then filtered. The filtrate was concentrated to dryness to obtain the title compound 25c 15 (0.75 g, 86.74%).
LC-MS (ESI): m/z = 225.1 [M+Hr.
Step 3: (1R,2R)-N-(4-(4-(((S)-2-amino-2,4-dimethylpent-4-en-l-yl)oxy)-3-cyanophenyl)pyri din-2-y1)-2-fluorocyclopropane- 1-carboxami de (compound 25) 5b (391 mg, 1.26 mmol), 25c (0.42 g, 1.89 mmol) and potassium carbonate 20 (0.35 g, 2.52 mmol) were sequentially added to a mixed solution of dioxane (50 mL) and water (10 mL). After nitrogen replacement, chloro(2-dicyclohexylphosphino-2',4',6'-trii sopropy1-1,1'-bipheny1)[2-(2'-amino-1,1'-biphenyl)Ipalladium (II) (0.01 g, 0.13 mmol) was added. After additional nitrogen replacement, the resulting mixture was reacted for 5 hours while the temperature 25 was maintained at 80 C. After the reaction was complete, the reaction mixture was filtered and concentrated and the residue was separated and purified by reverse phase column chromatography (C18 spherical 20-35 nm 100A 120 g; water :
acetonitrile (v/v) = 99 : 5-2: 1) to obtain compound 25 (160 mg, 31.06%).
LC-MS (EST): m/z = 409.3 [M+Hr.
30 NMR (400 MHz, DMSO-d6) 6 10.92 (s. 1H), 8.40- 8.35 (m, 2H), 8.13 -8.00 (m, 2H), 7.46 - 7.37 (m, 2H), 5.05 - 5.00 (m, 1H). 4.86 - 4.71 (m, 3H), 3.89 (s, 2H), 2.24 (s, 3H), 1.82 - 1.60 (m, 5H), 1.15 (s, 4H).
Example 26 (S)-14(2',6-bis(difluoromethy1)42,4'-bipyridinl-5-y1)oxy)-3-cyclopropyl-2-methylpropan-2-amine (compound 26) -s TBDPS
ci Step 1 Step 2 ON
TBDPSOThr"7 0 0 0 Step 3 26a 26h 26c 26d TBDPSO F N

Step 4 Step 5 HO 7, c= 22a F
F
0,eH
Step 6 26e 26f Compound 26 Step 1: 1-cyclopropy1-3-hydroxypropan-2-one (26b) 5 26a (2.5 g, 21.1 mmol) and tris(trimethylsilyloxy)ethylene (13.6 g, 46.4 mmol) were sequentially added to a sealed tube. The mixture was purged with nitrogen for 2 minutes and reacted at 80 C for 12 hours. The mixture was then cooled to room temperature. Hydrochloric acid (2 M, 30 mL) and THF (30 mL) were added. The resulting mixture was reacted at 80 C for 2 hours and then extracted with EA twice. The organic phase was washed with saturated sodium bicarbonate and then water, dried over anhydrous sodium sulphate and concentrated to obtain the title compound 26b as a light yellow oil (1.0 g, 41%), which was directly used in the next reaction.
LC-MS (EST): mlz = 115.1 [M+Hr.
15 Step 2: 1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropylpropan-2-one (26c) 26b (1.5 g, 13.1 mmol) was dissolved in DCM (30 mL) in a single-necked flask, and TEA (3.99 g, 39.4 mmol) and DMAP (0.16 g, 1.31 mmol) were added.
Subsequently, TBDPSC1 (4.33 g, 15.8 mmol) was added. The resulting mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was washed with water, dried over anhydrous sodium sulphate and concentrated. The residue was purified by column chromatography (PE : EA =

30: 1) to obtain compound 26c as a colourless oil (1.9 g, 41%).
LC-MS (EST): = 353.2 [M+Hr.
Step 3: (S)-N-(1- ((tert-butyl di phenyl si lyl)oxy)-3-cycl opropylpropan-2-25 ylidene) -2-m ethylpropane-2-sulphi nami de (26d) 26c (1.9 g, 5.39 mmol) was dissolved in THF (30 mL) in a single-necked flask and then S-tert-butylsulphinamide (0.80 g, 6.47 mmol) was added.
Subsequently, Ti(OiPr)4 (4.6 g, 16.17 mmol) was added. The mixture was subjected to nitrogen replacement 3 times and reacted at 80 C for 20 hours.
After 5 the reaction was completed, saturated brine was added to quench the reaction. The mixture was then extracted with ethyl acetate twice. dried over anhydrous sodium sulphate and concentrated to obtain the title compound 26d as a yellow oil (1.0 g, 40%), which was directly used in the next reaction.
LC-MS (EST): m/z = 456.2 [M-1-HI.
10 Step 4: N-((S)-1-((tert-butyldiphenylsilyl)oxy)-3-cyclopropy1-2-methylpropan -2-y1)-2-methylpropan e-2-sulphinami de (26e) Methylmagnesium bromide (1.31 g, 11 mmol) was dissolved in DCM (20 mL) and the mixture was stirred at 0 C. Then a solution of 26d (1.0 g, 2.19 mmol) in DCM was added dropwise to the reaction flask. The reaction mixture was 15 reacted at this temperature for 3 hours. After the reaction was completed, a large quantity of water was added to quench the reaction. Then the mixture was exacted with DCM twice. The organic phases were combined and dried over anhydrous sodium sulphate and the solvent was removed. Subsequently, the residue was separated by column chromatography (petroleum ether : ethyl acetate (v/v) = 10 :
20 1) to obtain compound 26e as a colourless oil (0.6 g, 58%).
LC-MS (EST): m/z = 472.2 [M+1-11+.
Step 5: (S)-2-amino-3-cyel opropy1-2-methylpropan- 1-ol (260 26e (0.6 g, 1.27 mmol) was dissolved in dioxane (5 mL) and then concentrated hydrochloric acid (5 mL) was added. Subsequently, the mixture was 25 reacted at 100 C for 5 hours. After the reaction was completed, the reaction solution was adjusted to a basic pH with ammonia in methanol. Then the solvent was completely removed by rotary evaporation. Subsequently, the residue was separated by column chromatography (dichloromethane : methanol (v/v) = 10 : 1) to obtain compound 26f as a colourless oil (80 mg, 48%).
30 LC-MS (EST): m/z = 130.1 [M+Hr.
Step 6: (S)-14(2',6-bis(difluoromethy1)42,4'-bipyridin]-5-y1)oxy)-3-cyclopropyl-2-methylpropan-2-amine (compound 26) 26f (80.0 mg, 0.62 mmol) was added to a sealed tube and then TI-IF (10 mL) was added. Subsequently, 22a (230.0 mg, 0.83 mmol) and potassium tert-butoxide (208.3 mg, 1.86 mmol) were sequentially added and the mixture was purged with nitrogen for 2 minutes and reacted at 80 C for 4 hours. After the reaction was completed, THF was removed by rotary evaporation. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL) twice. The organic phases were combined, dried over anhydrous sodium sulphate and concentrated.
The residue was then separated by column chromatography (dichloromethane :
methanol (v/v) = 20: 1) to obtain the title compound 26 (28 mg. 11%).
114 NMR (400 MHz, CDC13) 8.73 (d, 114), 8.20 (s, 114), 8.01 (d, 114), 7.94 (d, 1H), 7.44 (d, 1H), 7.02-6.57 (m, 2H), 4.03 (q, 2H), 1.64-1.36 (m, 2H), 1.36 (s, 3H), 0.75-0.70 (m, 1H), 0.53-0.48 (m, 2H), 0.15-0.08 (m, 2H).
LC-MS (EST): m/z = 384.2 [M+Hr.
Example 27 Methyl (5((2-ami no-2,4-dim ethylpent-3 -en-l-yeoxy)-4-(tri fluorometh y1)-[2,42-bipyridin1-21-yl)carbamate (compound 27) Step 1 Step HC)-(DH Step Step 2 .._HOOTBDPS
NH2 -w HN , HN 'Boo NH
Boo Boo' 27a 27b 27c 27d P hYP h 0 N
27e __________________________ TBDIDSC Step 5 9a I CF3 --Step 4 BOG_Doe N H Step 6 HN , Boo 27f 279 27h Step 7 cF,I
N
Compound 27 NI-12 Step 1: Tert-butyl (1,3-dihydroxy-2-methylpropan-2-yl)carbamate (27b) 27a (10 g, 95.11 mmol) was dissolved in 125 mL of (Me0H : THF = 100:
25) and di-tert-butyl dicarbonate (31.14 g, 142.67 mmol) was added while the mixture was cooled to 0 C in an ice bath. Sodium bicarbonate (15.98 g. 190.22 mmol) was added with stirring. After stirring, the mixture was transferred to room temperature and reacted for 12 hours. The reaction process was monitored by TLC.
After the reaction was complete, the reaction mixture was extracted with ethyl acetate and washed with water. The organic phase was dried over anhydrous sodium sulphate and concentrated to obtain a crude, which was separated by silica gel column chromatography (petroleum ether : ethyl acetate = 2 : 1) to obtain 18 g of the title compound 27b (yield: 92%).
LC-MS (ESI): m/z = 150.2 [M+H-tBur.
Step 2: Tert-butyl N-(1-Rtert-butyldiphenyl silyl)oxy1-3-hydroxy-2-5 methylpropan-2-yl)carbamate (27c) Compound 27b (18 g, 87.69 mmol) and imidazole (5.98 g, 87.69 mmol) were dissolved in DMF (200 mL). The mixture was cooled to 0 C. TIMPSC1 (20.46 mL, 78.92 mmol) was slowly added. The resulting mixture was stirred at room temperature overnight. Water was added and the resulting mixture was extracted with EA. Liquid separation was performed. The organic phase was washed with water and liquid separation was performed, followed by extraction with saturated brine and additional liquid separation. The organic phase was dried, concentrated and subjected to rotary evaporation to obtain a crude, which was separated and purified by column chromatography (petroleum ether : ethyl acetate = 10 : 1) to 15 obtain compound 27c (20 g, 51%).
LC-MS (EST): m/z = 444.3 [M+Hr.
Step 3: Tert-butyl (1-((tert-butyldi phenyl sil yl)oxy)-2-m ethyl-3-oxopropan-yl)carbamate (27d) Compound 27c (20 g, 45 mmol) was dissolved in acetone (400 mL) and IBX
20 (19 g, 67.62 mmol) was added. The mixture was stirred at 60 C overnight.
The mixture was cooled to room temperature, filtered by suction and washed with EA.
The filtrate was concentrated and subjected to rotary evaporation to obtain compound 27d (18 g, 90%).
LC-MS (EST): m/z = 344.1 [M+H-Bocr.
25 Step 4: Tert-butyl (1 -((tert-b utyl di ph en yl silye o x y)-2,4-dimeth ylpent- 3-en-2-yl)carbamate (270 Compound 27e (14.1 g, 32.61 mmol) was dissolved in THF (100 mL). Under nitrogen protection, the mixture was cooled to 0 C and n-butyllithium (1.6 M, 20.37 mL) was added. The resulting mixture was stirred at 0 C for 5 minutes and 30 cooled to -78 C and a solution of compound 27d (6 g, 13.59 mmol) in 30 mL of THF was added. At -78 C, the mixture was reacted for 30 minutes, transferred to an ice-water bath, and reacted for another 1 hour. The reaction was quenched by saturated NIT4C1. The mixture was extracted with EA and liquid separation was performed. The organic phase was dried and concentrated and the residue was separated and purified by column chromatography (petroleum ether : ethyl acetate = 10: 1) to obtain the crude product of compound 27f (0.5 g).
LC-MS (EST): m/z = 468.2 [M+Hr.
Step 5: Tert-butyl (1-hydroxy-2,4-dimethylpent-3-en-2-yl)carbamate (27g) 5 Compound 27f (0.5 g, 1.07 mmol) was dissolved in TI-IF (5 mL) and TBAF
(1 M, 2 mL) was added. The mixture was stirred at room temperature overnight, concentrated and subjected to rotary evaporation. The residue was separated and purified by column chromatography (dichloromethane : methanol = 10 : 1) to obtain compound 27 g (170 mg).
10 LC-MS (EST): m/z = 174.2 [M+H-tBur.
NMR (400 MHz, CDC13) 8 5.25 (m, 114), 4.87 (s, 1H), 3.78 (d, 11-1), 3.52(d, 1H), 1.78 (d, 3H), 1.73 (d, 3H), 1.43 (s, 9H), 1.38 (s, 3H).
Step 6: Tert-butyl (14(2'-((methoxycarbonyl)amino)-4-(trifluoromethyl)-[2,4:_ bipyri din1-5-yl)oxy)-2,4-dimethylpent-3-en-2-yl)earbamate (27h) 15 Compound 9a (84 mg, 0.27 mmol) and a solution of 1M potassium tert-butoxide in THF (0.4 mL) were stiffed at room temperature for 5 min and compound 27g (61 mg, 0.26 mmol) was added. After nitrogen replacement, the mixture was warmed to 80 C and stirred overnight. After the reaction was completed, the reaction mixture was concentrated and the crude was separated and 20 purified by column chromatography (dichloromethane : methanol = 10 : 1) to obtain the title compound 27h (23 mg, 17%).
LC-MS (EST): m/z = 525.2 [M+Hr.
Step 7: Methyl (5-((2-amino-2.4-dimethylpent-3-en- 1-ypoxy)-4-(trifluoromethyl)-[2,4'-bipyridin1-2'-yl)carbamate (compound 27) 25 Compound 27h (23 mg, 0.04 mmol) was dissolved in dichloromethane (2 mL) and TFA (0.3 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and subjected to rotary evaporation. The residue was purified by HPLC to obtain the title compound 27 (5 mg, 27%).
30 LC-MS (EST): m/z = 425.2 [M-1-Hr.
11-1 NMR (400 MHz, CD30D) ô 8.79 (s, 1H), 8.54 (s, 1H), 8.35 (d, 1H), 8.17 (s, lH), 7.68 (dd, 1H), 5.36 (s, 1H), 4.53 (d, 1H), 4.44 (d, 1H), 3.80 (s, 3H), 1.89 (d, 3H), 1.87 (d, 31-I), 1.72 (s, 31-I).
19F NMR (376 MHz, CD30D) 6 -62.71.

Example 28 N-(4-(4-(((2S)-2-amino-4,5-dihydroxy-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-yl)acetamide (compound 28) AN
CN
Step 1 Ail CN
_________________________________________________________ H OCIOH
H2N H21,1 Compound 5 Compound 28 OH
5 Step 1: N-(4-(4-(((2S)-2-amino-4,5-dihydroxy-2,4-dimethylpentyl)oxy)-3-cyanophenyl)pyridin-2-ye acetamide (28) Compound 5 (100 mg, 0.27 mmol), potassium osmate dihydrate (10 mg, 0.027 mmol) and N-methylmorpholine oxide (95 mg, 0.81 mmol) were dissolved in water (1 mL) and acetone (3 mL). The mixture was reacted at room temperature for 3 hours and then purified by C-18 reverse phase column chromatography (acetonitrile : water = 40 : 60) to obtain compound 28 (50 mg, 46%).
LC-MS (EST): ink = 399.51M+Hr.
11-1 NMR (400 MI-1z, DMSO-d6) 6 10.55 (s, 114), 8.37 ¨ 8.32 (m, 21-1), 8.12 (d, 11-1), 7.98 (d, 1H), 7.45 ¨ 7.36 (m, 211), 4.87 ¨4.83 (m, 11-1), 4.71 (s, 11-1), 3.88 (s, 15 2H), 2.23 (s, 2H), 2.12 (s, 3H), 1.79 (s, 3H), 1.54 (s, 2H), 1.14 (s, 3H).
Examples 29 and 30 (1R)-N-(4-(4- [(2S)-2-amino-2,4-dimethylpent-4-en-l-yll oxy1-3-cyan oph enyl)pyri din-2-y1)-2,2-di fluorocyclopropan e-l-carb ox ami de and (1S)-N-(4-(4-{ [(2S)-2-amino-2,4-dimethylpent-4-en-1-yll oxy1-3-cyanophenyl)pyri din-20 y1)-2,2-difluorocyclopropane- 1 -carbox amide (compound 29 and compound 30) Step 1 F NT Step 2 5b FVN' -'13r FFV)1'19¨`
H2r4"-iBr Step 3 OH
4A 29b 29c o N
õ,JLNCN
H

Chiral F F -0-Fv,AN
I CN
preparation H2N ' CN
29d F F

Compound 29 Compound 30 Step 1: N-(4-bromopyridin-2-y1)-2,2-difluorocyclopropane-l-carboxamide (29b) 4A (2.00 g, 11.56 mmol), 2,2-difluoro-clopropanecarboxylic acid (1.41 g, 11.56 mmol), N-methylimidazole (1.90 g, 23.12 mmol) and N,N.N',N'-tetramethylchloroformamidinium hexafluorophosphatc (3.89 g, 13.87 mmol) were sequentially added to dichloromethane (50 mL), and after nitrogen replacement, the mixture was stirred overnight. After the reaction was complete, water (50 mL) was added and the mixture was washed with saturated sodium bicarbonate (50 mL). The aqueous phase was extracted with dichloromethane (50 mL). The organic layers were combined, dried over anhydrous sodium sulphate and filtered. The filtrate was subjected to rotary evaporation and the residue was purified by silica gel column (petroleum ether : ethyl acetate (v/v) = 99 : 1-2 : 1) to obtain intermediate 29b (5.20 g, 69%).
LC-MS (EST): m/z = 277.0 [M+Hr.
15 Step 2: (2-(2,2-difluorocyclopropaneami do)pyridin-4-yl)boronic acid (29c) 29b (800 mg, 2.89 mmol). potassium acetate (850 mg, 8.67 mmol) and bis(pinacolato)diboron (1.10 g, 4.33 mmol) were sequentially added to a mixed solution of di oxane (50 mL) and water (10 mL). After nitrogen replacement, 11,1'-bis(diphenylphosphino)ferrocenelpalladium dichloride (II) (0.11 g, 0.14 mmol) 20 was added.
After additional nitrogen replacement, the mixture was reacted for 3 hours while the temperature was maintained at 80 C. The reaction process was monitored with LC-MS. After the reaction was complete, the mixture was cooled to room temperature and filtered. The filtrate was concentrated to dryness.
Acetonitrile (200 mL) was added and the resulting mixture was ultra-sonicated for 25 15 min and then filtered. The filtrate was concentrated to dryness to obtain intermediate 29c (0.5 g, 71%).
LC-MS (ESI): m/z = 243.1 [M+Hr.
Step 3: N-(4-(44(S)-2-amino-2,4-dimethylpent-4-en-l-yeoxy)-3-cyan oph enyl)pyri din-2-y1)-2,2-difluorocycl opropan e-l-carb ox ami de (29d) 30 5b (500 mg, 1.61 mmol), 29c (0.97 g, 4.03 mmol) and potassium carbonate (0.67 g, 4.83 mmol) were sequentially added to a mixed solution of dioxane (100 mL) and water (20 mL). After nitrogen replacement, chloro(2-dicyclohexylphosphino-2',4',6'-trii sopropy1-1,1'-bipheny1)[2-(2'-amino-1,1'-bipheny1)1palladium (II) (0.01 g, 0.13 mmol) was added. After additional nitrogen replacement, the resulting mixture was reacted for 5 hours while the temperature was maintained at 80 C. After the reaction was complete, the reaction mixture was filtered and concentrated and the residue was separated and purified by reverse phase column chromatography (C18 spherical 20-35 nm 100A 120 g; water :
5 acetonitrile (v/v) = 99 : 5-2: 1) to obtain compound 29d (420 mg, 61.17%).
LC-MS (EST): m/z = 427.2 [M+Hr.
IT-T NMR (400 MI-Tz, DMSO-d6) 6 11.10 (s, 114), 8.46¨ 8.25 (m, 21-1), 8.14 (m, 114), 8.01 (m, 11-1), 7.50 (m, 114), 7.37 (m, 114), 4.86 (m, 114), 4.70 (m, 11-1), 3.89 (s, 2H), 3.14 ¨ 2.92 (m, 1H), 2.23 (s, 2H), 2.15¨ 1.93 (m, 2H), 1.70 (m. 5H), 1.15 (s, 10 3H).
Chiral preparation 29d (420 mg) was subjected to chiral resolution to obtain two isomers: Pi (151 mg, retention time: 1.264 minutes, set to be compound 29) and P2 (150 mg, retention time: 2.080 minutes, set to be compound 30).
15 Preparation method:
instrument: MG II preparative SFC (SFC- 14); column: ChiralPak IC, 250 x 30 mm I.D., 10 1,1m; mobile phase: A, CO2 B, ethanol (0.1% NI43=H20):
gradient:
35% 13 gradient elution; flow rate: 80 mL/min; column temperature: 38 C;
wavelength: 220 nm; cycle time: 5.5 min; sample preparation: sample 20 concentration: 11.25 mg/mL, dichloromethane/methanol solution; sample injection: 1 ml/injection. After separation, the fractions were dried on a rotary evaporator at the bath temperature of 40 C to obtain the desired isomers, respectively.
Examples 31 and 32 25 Methyl (S)-(5-(2-amino-3-cyclopropy1-2-methylpropoxy)-6-(difluoromethyl)-[2,4'-bipyridird-2'-yl)carbamate and methyl (R)-(5-(2-amino-3-cyclopropy1-2-methylpropoxy)-6-(difluoromethyl)-[2,4'-bipyridin1-2'-yl)carbamate (compound and compound 32) H2N.s.k 8 ________________________________________________________ oõ8 TBDPSO TBDPSOM Step 2 TBDPS0*`v Step 3 ,NHHO
0,s,N

Step 1 26c 31a 31b 31c in 7 N F N Chiral Oa F preparation Hp Step 4 o N".

31d F
077, 1-121,1 v Compound 31 Compound 32 Step 1: N- (1-((tert-butyldi ph enyl silyeoxy)-3- cyclopropylpropan-2-yli den e)-2-methylpropane-2- sulphinami de (31a) 26c (1.9 g, 5.39 mmol) was dissolved in THF (30 mL) in a single-necked flask and then tert-butylsulphinamide (0.80 g, 6.47 mmol) was added.
Subsequently, Ti(Oi-Pr)4 (4.6 g, 16.17 mmol) was added. The mixture was subjected to nitrogen replacement 3 times and reacted at 80 C for 20 hours.
After the reaction was completed, saturated brine was added to quench the reaction.
The mixture was then extracted with ethyl acetate twice, dried over anhydrous sodium sulphate and concentrated to obtain the title compound 31a as a yellow oil (1.0 g, 40%), which was directly used in the next reaction.
LC-MS (EST): m/z = 456.2 [M+Hr.
Step 2: N-(- 1-((tert-butyl di ph enyl silyl)oxy)-3-cycl opropyl -2-m eth ylpropan-2-y1)-2-methylpropan e-2- sulphin ami de (31b) Methylmagnesium bromide (1.31 g, 11 mmol) was dissolved in DCM (20 mL) and the mixture was stirred at 0 C. Then a solution of 31a (1.0 g, 2.19 mmol) in DCM was added dropwi se to the reaction flask. The reaction mixture was reacted at this temperature for 3 hours. After the reaction was completed, water was added to quench the reaction. Then the mixture was exacted with DCM twice.
The organic phases were combined and dried over anhydrous sodium sulphate and the solvent was removed. Subsequently, the residue was separated by silica gel column chromatography (petroleum ether : ethyl acetate (v/v) = 10 : 1) to obtain compound 31b as a colourless oil (0.6 g, 58%).
LC-MS (ESI): m/z = 472.2 [M+Hr.
Step 3: 2-amino-3-cyclopropy1-2-methylpropan-l-ol (31c) - 89 -31b (0.6 g, 1.27 mmol) was dissolved in dioxane (5 mL) and then concentrated hydrochloric acid (5 mL) was added. The mixture was reacted at 100 C for 5 hours. After the reaction was completed, the reaction solution was adjusted to a basic pH with ammonia in methanol. Then the solvent was 5 completely removed by rotary evaporation. Subsequently, the residue was separated by silica gel column chromatography (DCM: methanol (v/v) = 10: 1) to obtain compound 31c as a colourless oil (80 mg, 48.7%).
LC-MS (EST): m/z = 130.1 [M+Hr.
Step 4: Methyl (5-(2-amino-3-cyclopropy1-2-methylpropoxy)-6-(difluoromethyl) 10 42,4'-bipyridin1-2'-yl)carbamate (31d) 31c (80.0 mg, 0.62 mmol) was added to a sealed tube and then TI-IF (10 mL) was added. 9a (221.0 mg, 0.74 mmol) and potassium tert-butoxide (208.3 mg, 1.86 mmol) were sequentially added and the mixture was purged with nitrogen for 2 minutes and reacted at 80 C for 4 hours. After the reaction was completed, TI-IF
15 was removed by rotary evaporation. Water (50 mL) was added and the mixture was extracted with ethyl acetate (50 mL) twice. The organic phases were combined and dried over anhydrous sodium sulphate, and the solvent was removed. The residue was then separated by column chromatography (dichloromethane :
methanol (v/v) = 20: 1) to obtain the title compound 31(1 (140 mg, 55.7%).
20 11-1 NMR (400 MHz, CDC13) a 8.53 (s, 1H), 8.36 (m. 11-1), 7.95 (m, 1H), 7.71 (d, 1H), 7.39 (d, 11-1), 6.84 (t, 1H), 3.95 (q, 2H), 3.85 (s, 3H), 1.60-1.47 (m, 2H), 1.31 (s, 3H), 0.77-0.70 (m, 1H), 0.53-0.48 (m, 2H), 0.15-0.08 (m, 2H).
LC-MS (EST): m/z = 407.2 [M+Hr.
Chiral preparation 25 31d (140 mg) was subjected to chiral resolution to obtain two isomers: Pi (60 mg, retention time: 1.847 minutes, set to be compound 31) and P2 (60 mg, retention time: 2.203 minutes, set to be compound 32).
Preparation method:
instrument: Waters 150 MGM; column: Chiralpak Column; mobile phase: A, 30 CO2, B, IPA
(0.1% N1-13.1-120); gradient: 40% B gradient elution; flow rate: 80 mL/min; column temperature: 35 C; wavelength: 220 nm; cycle time: 7.6 min;
sample preparation: sample concentration: 6.0 mg/mL, acetonitrile solution;
sample injection: 2.5 ml/injection. After separation, the fractions were dried on a rotary evaporator at the bath temperature of 30 C to obtain Pi and P2. Then the products were dried in a lyophilizer at -80 C for removing the solvent to obtain Pi and P2.
Biological test 1. In vitro AAK1 enzyme activity assay 5 Compound stock solution (concentration: 10 mM, dissolved in DMSO) was diluted with DMSO to 0.2 mM and then diluted with DMSO in 5-fold gradient to obtain compound solutions with 10 concentrations. Subsequently, the compound solutions with different concentrations were diluted 50-fold in lxkinase reaction buffer (containing 40 mM Tris, 20 mM MgCl2, 0.1% BSA and 0.5 mM DTT) for 10 later use.
AAK1 (Signalchem, Cat# A01-11G-10) was diluted with 1 xkinase reaction buffer to 2-fold the final concentration (final concentrations: 30 nM
and 28 nM). AAK1 was added to a 384-well white plate at 2 uL/well, and the compounds were then added at 1 uL/well. The plate was sealed with a plate-sealing film, centrifuged at 1000 rpm for 30 seconds and then placed at room 15 temperature for 10 minutes. A mixed solution of ATP (Promega, Cat# V914B) and substrate Micro2 (GenScript, Cat# PE0890) was formulated at 4-fold the final concentration (for AAK1, the corresponding final concentrations of ATP: 15 vilVI
and 5 uM, and the corresponding final concentration of Micro2: 0.1 mg/mL). To the reaction plate was added the mixed solution of ATP and the substrate at 1 20 IlL/well. The plate was sealed with a plate-sealing film and centrifuged at 1000 rpm for 30 seconds. The reaction was carried out at room temperature for 60 minutes (AAK1). ADP-Glo (Promega, Cat# V9102) was transferred to the 384-well plate at 4 L/well and centrifugation was carried out at 1000 rpm for 1 minute. The mixture was incubated at 25 C for 40 minutes. A detection solution 25 was transferred to the 384-well plate at 8 uL/well and centrifugation was carried out at 1000 rpm for 1 minute. The resulting mixture was incubated at 25 C for minutes. The RLU (Relative luminescence unit) signal values were read using a Biotek multilable microplate reader and the percent inhibition was calculated according to the following formula: [1-(LUMcompound-LUMpositive control) 30 (LUM
¨negative control-LUMpositive control)] X 100. IC50 values were calculated using Graphpad 7.0 software using a four-parameter non-linear fit equation. The specific results are shown in Table 1.
Table 1 Inhibitory activity against AAK1 Compound No. 1C50/nM

Compound 1 14.72 Compound 2 9.29 Compound 3 10.92 Compound 5 6.37 Compound 6 10.97 Compound 7 13.81 Compound 10 11.47 Compound 11 5.74 Compound 13 10.57 Compound 14 12.62 Compound 15 19.82 Compound 16 22.26 Compound 17 26.77 Compound 18 9.55 Compound 19 37.73 Compound 20 16.06 Compound 21 13.74 Compound 22 32.08 Compound 23 38.62 Compound 24 22.46 Compound 25 11.94 Compound 26 11.01 Compound 27 43.09 Compound 28 5.96 Compound 29 10.98 Compound 30 9.08 Compound 31 10.92 Conclusion: the compounds of the present invention show relatively high inhibitory activity against the AAK1 receptor.
2. Pharmacokinetic test in beagle dogs Experimental animals: male beagle dogs, about 8-11 kg, 6 beagle 5 dogs/compound, purchased from Beijing Marshall Biotechnology Co., Ltd.
Experimental method: on the day of the experiment, 12 beagle dogs were randomly grouped according to their body weights. the animals were fasted with water available for 12 to 14 h one day before the administration, and were fed 4 h after the administration; and the administration was performed according to Table 10 2.

Table 2. Administration information Number Administration information Administration Administration Group Test Administration Collected Mode of Male concentration volume compounds dosage (mg/kg) sample administration (mg/mL) (mL/kg) Cl 3 1 1 1 Plasma Intravenously G2 3 3 0.6 5 Plasma Intragastrically G3 3 Compound 1 1 1 Plasma Intravenously G4 3 19 3 0.6 5 Plasma Intragastrically Notes: Vehicle for intravenous administration: 5% DMA+5% Soluto1+90%
Saline; vehicle for intragastric administration: 0.5% MC
(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate;
5 Saline: physiological saline; MC: methylcellulose) Before and after the administration, 1 ml of blood was taken from the jugular veins or limb veins, and placed in an EDTAK2 centrifuge tube. Centrifugation was performed at 5000 rpm at 4 C for 10 min, and plasma was collected. Blood sampling time points for both the LX9211 intravenous administration group and 10 intragastric administration group include: 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, and 24 h, and blood sampling time points for both the compound 19 intravenous administration group and intragastric administration group include: 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 48 h. Before analysis and detection, all samples were stored at -80 C.
The 15 samples were analysed quantitatively by LC-MS/MS. The experimental results are shown in Table 3.
Table 3. Pharmacokinetic parameters of test compounds in plasma of beagle dogs Test Mode of CL Vdss AUCo-t F (%) compounds administration (mL/m in/kg) (L/kg) (hrxng/mL) i.v. (1 mg/kg) 22.2 7.7 9.08 1.4 751 i.g. (3 mg/kg) 500 183 22.2 8.1 i.v. (1 mg/kg) 39.8 10 23.6 3.8 398 94 Compound 19 i.g. (3 mg/kg) 1353 83 113 6.9 -: not applicable.
.N.
y -F
Notes: LX-9211 has a structure of H2r4 20 Conclusion: Conclusion: The compounds of the present invention possess good pharmacokinetic characteristics.

3. Test for hERG potassium ion channel Experimental platform: electrophysiological manual patch-clamp system Cell line: Chinese hamster ovary (CHO) cell lines stably expressing hERG
potassium ion channel 5 Experimental method: In CT-TO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel, whole cell patch-clamp technique was used to record hERG potassium channel current at room temperature. The glass microelectrode was made of a glass electrode blank (BF150-86-10, Sutter) by a puller. The tip resistance after filling the liquid in the electrode was about 2-5 MQ.
The glass microelectrode can be connected to the patch-clamp amplifier by inserting the glass microelectrode into an amplifier probe. The clamping voltage and data recording were controlled and recorded by the pClamp 10 software through a computer. The sampling frequency was 10 kHz, and the filtering frequency was 2 kHz. After the whole cell records were obtained, the cells were 15 clamped at -80 mV, and the step voltage that induced the hERG potassium current hERG) was depolarized from -80 mV to +20 mV for 2 s, then repolarized to -50 mV, and returned to -80 mV after 1 s. This voltage stimulation was given every s, and the administration process was started after the hERG potassium current was confirmed to be stable (at least 1 minute). The compound was administered for at 20 least 1 minute at each test concentration, and at least 2 cells (n > 2) were tested at each concentration.
Data processing: Data analysis processing was carried out by using pClamp 10, GraphPad Prism 5 and Excel software. The inhibition degree of hERG
potassium current (peak value of hERG tail current induced at -50 mV) at different 25 compound concentrations was calculated by the following formula:
Inhibition% = [1 ¨ (// /6)] x 100%
wherein, Inhibition % represents the percentage of inhibition of hERG
potassium current by the compound, and / and /o represent the amplitude of hERG
potassium current after and before dosing, respectively.
30 Compound IC50 was calculated using GraphPad Prism 5 software by fitting according to the following equation:
Y = Bottom + (Top-Bottom)/(1+10^((LogIC50-X)xHillSlope)) Among the equation, X represents the Log value of the tested concentration of the test sample, Y represents the inhibition percentage at the corresponding concentration, and Bottom and Top represent the minimum and maximum inhibition percentage, respectively.
Experimental results: IC50 values of the inhibitory effect of the test compounds on hERG potassium channel current are shown in Table 4.
5 Table 4 Inhibition of test compounds on hERG potassium channel current Inhibition rate at the highest Test compounds IC5o ( M) concentration tested LX-92 1 1 102.2 4.08%@40 tiM 1.82 Compound 3 86.6 1.77%@40 04 8.75 Compound 19 68.9 1.80%@40 04 24.1 4. Spinal nerve ligation (SNL)-induced mouse model of neuropathic pain Male C57BL/6J mice (8 weeks old) purchased from Jinan Pengyue Experimental Animal Breeding Co., Ltd. were adaptively raised for one week and then the models were established. The specific establishment method comprises the 10 following steps:
1) disinfecting the surgical instrument and ligature;
2) anesthetizing the mice with isoflurane and then placing the mice on the operating table in the prone position;
3) shaving the fur near the hip bones of the mice and preparing the skin, and 15 making an incision of about 2 cm along the spine;
4) isolating the fascia along the spine, performing blunt dissection of the muscles, and exposing the transverse process of L5;
5) carefully cutting the transverse process of L5 with forceps and exposing the L5 spinal nerve;
20 6) carefully isolating the L5 nerve with a glass dissecting needle, and ligating the L5 nerve with a 5-0 ligature; and 7) suturing the muscles and skin and disinfecting same with iodophor.
The mice that were unsuccessful in modeling were eliminated the next day after modeling (marker for successful modeling: mice with their hind paws curled 25 up). After modeling, the mice were stroked for 3 to 5 minutes every day to ensure that the animals were familiar with the experimenter, and then the mice were placed on a metal pain measuring frame for 40 to 60 minutes of adaptation.
After 3 days of acclimatization, Von Frey filaments (Aesthesioa 0.16 g, 0.4 g, 0.6 g, 1.0 g, 1.4 g and 2.0 g) were used to test the pre-administration baseline values of the animals (Ascending testing approach). Each animal was tested twice and average values were taken, with intervals of at least 5 minutes. The animals were grouped according to the baseline values (10 animals per group). After the grouping, LX-9211(1 and 10 mg/kg), compound 3(1 and 10 mg/kg) or vehicle (40% PEG-400 +
5 10% ethanol +
15% Twecn 80 + 35% physiological saline) were administered intragastrically. The mice were tested for the mechanical pain threshold (MPT) at 1, 3 and 6 hours after the administration. Time-MPT curve was plotted using GraphPad 8.3.0, and statistical analysis was performed.
Results and conclusion: The results are shown in Figure 1. At 1, 3 and 6 hours 10 after a single administration, LX-9211 and compound 3 (both at the dose of 10 mg/kg) effectively increased the pain threshold of mice after SNL modelling.
The analgesic efficacy of LX-9211 (10 mg/kg) reached the peak at 1 hour after the administration, and the efficacy gradually decreased thereafter. The analgesic efficacy of compound 3 (10 mg/kg) reached the peak at 3 hours after the administration and tended to be stable at 1 hour to 6 hours after the administration.
Compound 3 had better efficacy than LX-92I I at 3 and 6 hours after the administration. The above data show that as an analgesic, compound 3 has better pharmacodynamic activity than LX-9211.
5. Mouse brain/blood ratio test 20 5.1 Experimental animals: Male ICR mice, 20-25 g, 9 mice/compound.
Purchased from Chengdu Ddossy Experimental Animals Co., Ltd.
5.2 Experimental design: on the day of the experiment, 18 ICR mice were randomly grouped according to their body weights. The animals were fasted with water available for 12 to 14 h one day before the administration, and were fed 4 h 25 after the administration;
Table 5. Administration information Number Administration information Administration Administration Group Administration Collected Mode of Male Test compounds concentration volume dosage (mg/kg) samples administration (mg/mL) (mL/kg) GI 9 LX92I 1 10 1 10 Plasma Intragastrically G2 9 Compound 3 10 1 10 Plasma Intragastrically Notes: Vehicle for intragastric administration: 40% PEG-400+10%
Ethano1+15% Tween 80+35% Saline;
(Saline; Ethanol; Tween 80) After intragastric administration, whole blood and brain tissue were collected at 0.5 h, 4 h and 24 h, and the whole blood was centrifuged to separate the plasma.
The brain tissue was rinsed with cold physiological saline to remove the residual blood on the surface, drained out and then homogenized. Before analysis and 5 detection, all samples were stored at -80 C. The samples were analyzed quantitatively by LC-MS/MS.
The test results are shown in Table 6.
Table 6. Pharmacokinetic parameters of compound in plasma of mice Brain tissue Test Mode of Plasma AUCo_t Brain/plasma AUCo_t compounds administration (heng/mL) ratio (hrng/g) LX9211 i.g. (10 mg/kg) 6643 110424 16.6 Compound 3 i.g. (10 mg/kg) 572 36853 64.5 -: not applicable.
10 Conclusion: The compounds of the present invention, especially compound 3, have a high brain penetrability.

Claims (15)

- 97 -I .
A compound of formula (I), or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, x2 x3 y3 (I) characterised in that X2, x3 and X4 are each independently selected from N or CW;
Yi, Y2 and Y3 are each independently selected from N or CW;
Z is selected from NW or 0;
W is selected from H, deuterium, halogen, C1_6 alkyl, halo C1_6 alkyl, or deuterated C 1_6 alkyl;
R' and W are each independently selected from H, deuterium, halogen, amino, nitro, cyano, hydroxyl, sulphonyl, C1_6 alkyl, halo Ci_6 alkyl, deuterated C1_6 alkyl, C1_6 alkoxy, halo C1-6 alkoxy, deuterated C1_6 alkoxy, hydroxy Ci_6 alkyl, C3-6 cycloalkyl, or 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents;
R1 and R2 are each independently selected from H, deuterium, halogen, amino, -COOH, cyano, sulphonyl, aminoacyl, C1_6 alkyl, halo Ci_6 alkyl, deuterated C1_6 alkyl, C1-6 alkoxy, halo C1_6 alkoxy, deuterated C1-6 alkoxy, hydroxy C1-6 alkyl, C3_6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, -NHC(0)C1-6 alkyl, -NHC(0)C3-6 cycloalkyl, -NHC(0)C4-6 heterocycloalky I, -NHC(0)NHC 1-6 alkyl, or -NHC(0)0C1_6 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents;
R31 and R32 are each independently selected from H, deuterium, halogen, cyano, hydroxyl, C1-6 alkyl, halo C1_6 alkyl, deuterated C1_6 alkyl, C1_6 alkoxy, halo C1_6 alkoxy, deuterated C1-6 alkoxy, or hydroxy C1-6 alkyl; or R31 and R32 together with the carbon atom to which they are attached form C3_6 cycloalkyl or 4- to membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with

1-3 RA substituents;
R41 and R42 are each independently selected from H, deuterium, amino, CI 6 5 alkyl, halogen, cyano, hydroxyl, halo CI-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo CI-6 alkoxy, -C1_6 alkyl-C3_6 cycloalkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, deuterated CI-6 alkoxy, or hydroxy C1-6 alkyl;
or R41 and R42 together form C3-6 cycloalkyl or 4- to 6-membered 10 heterocycloalkyl containing 1 heteroatom selected from 0 or S, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA

substituents;
R51 and R52 are each independently selected from H, deuterium, amino, halogen, C1-6 alkyl, cyano, hydroxyl, halo C1-6 alkyl, deuterated C1-6 alkyl, 15 alkoxy, halo C1-6 alkoxy, -C1_6 alkyl-C3_6 cycloalkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, deuterated CI 6 alkoxy, or hydroxy CI 6 alkyl;
or R51 and R52 together with the carbon atom to which they are attached form C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms 20 selected from N, S and 0, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents;
R61, R62 and K,-.63 are each independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, C1_6 alkyl, halo C1-6 alkyl, deuterated C1-6 alkyl, C1-alkoxy, halo C1-6 alkoxy, -C1_6 alkyl-C3_6 cycloalkyl, C3-6 cycloalkyl, 4- to 25 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S
and 0, deuterated C1_6 alkoxy, or hydroxy C1-6 alkyl;
or, R31 and R41. or R41 and R51 together with the carbon atoms to which they are each attached form C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the cycloalkyl and 30 heterocycloalkyl are optionally further substituted with 1-3 RA
substituents;
or, R41 and R61, or R7 and R41 together with the atoms to which they are each attached form C4-6 cycloalkyl or 4- to 6-membered heterocycloalkyl containing heteroatoms selected from N, S and 0, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents;

or, R51 and R61, or R61 and R62 together with the carbon atom(s) to which they are each attached form C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, or a double bond, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-5 substituents;
or, R61, R62 and R63 together with the carbon atom to which they are attached form C5_10 bridged ring or Csii spiro ring, wherein the bridged ring and spiro ring are optionally further substituted with 1-3 RA substituents;
RA is selected from deuterium, halogen, amino, cyano, hydroxyl, C1-6 alkyl, 10 halo Ci_6 alkyl, deuterated CI _6 alkyl, CI -6 alkoxy, halo C _6 alkoxy, deuterated CI -6 alkoxy, or hydroxy CI -6 alkyl, R31 ,R32 R51 R52 <-R63 R., R42 provided that when Z is selected from 0, R61 does not form the following structures:
, H2N and

2. The compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to claim 1, having a structure of formula (Ia):
N

y2 R62 R61 (Ia).

3. The compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to claim 1 or 2, characterised in that R1 is selected from sulphonyl, aminoacyl, halo C1-3 alkyl, -NHC(0)C1_4 alkyl, 25 -NHC(0)C1-6 cycloalkyl, -NHC(0)C4_6 heterocycloalkyl, -NHC(0)NHCI -4 alkyl, or -NI-IC(0)0C1_4 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 RA substituents;

R2 is selected from cyano, CI -3 alkyl, halo CI -3 alkyl, or deuterated Ci -3 alkyl;
RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1-3 alkyl, halo CI -3 alkyl, deuterated C1-3 alkyl, CI -3 alkoxy, halo C1-3 alkoxy, deuterated alkoxy, or hydroxy CI 3 alkyl.

4. The compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptabl e salt or co-crystal thereof according to claim 1, having a structure of formula (II):
r z7) 63 /c\

Re1 (m.

5. The compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to any one of claims 1-4, characterised in that Z is selected from NR' or 0;
R' is selected from H, deuterium or CI-4 alkyl;
R31 and R32 are each independently selected from H, deuterium, F, CI, cyano, hydroxyl, C -4 alkyl, halo C -4 alkyl, deuterated Ci _4 alkyl, CI _4 alkoxy, halo C1-4 alkoxy, deuterated CI _4 alkoxy, or hydroxy Ci _4 alkyl; or fel and R32 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, or 4- or 5-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 substituents selected from RA;
R4i and R42 arc each independently selected from H, deuterium, amino, C1-4 alkyl, halogen, cyano, hydroxyl, halo CI -4 alkyl, deuterated CI -4 alkyl, CI
_4 alkoxy, halo C1-4 alkoxy, -C1-4 alky1-3-membered cycloalkyl, -C1-4 alky1-4-membered cycloalkyl, -CI -4 alky1-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-. 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, deuterated C1-4 alkoxy, or hydroxy C1_4 alkyl; or R4i and R42 together form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4- or 5-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 substituents selected from RA;
5 R51 and R52 are each independently selected from 1-1, deuterium, amino, halogen, Ci_4 alkyl, cyano, hydroxyl, halo Ci_4 alkyl, deuterated Ci_4 alkyl, alkoxy, halo Ci_4 alkoxy, -Ci_a alky1-3-membered cycloalkyl, alky1-4-membered cycloalkyl, -CI _4 alky1-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, deuterated CI _4 alkoxy, or hydroxy CI-4 alkyl; or R51 and R52 together with the carbon atom to which they are attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, or 4-, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 substituents selected from RA;
R61 R62 and R63 are each independently selected from 1-1, deuterium, halogen, amino, cyano, hydroxyl, CI-4 alkyl, halo CI-4 alkyl, deuterated C1_4 alkyl, CI-al koxy, halo CI _4 al koxy, -CI _4 al ky1-3-m emb ered cycloalkyl, -C -4 alky1-4-20 membered cycloalkyl, -CI _4 alky1-5-membered cycloalkyl, 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, deuterated CI -4 alkoxy, or hydroxy C1-4 alkyl;
or, R31 and R41. or R41 and R51 together with the carbon atoms to which they 25 are each attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, or 4-, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 substituents selected from RA;
30 Or, R41 and R61 together with the carbon atom(s) to which they are each attached form 4-membered cycloalkyl, 5-membered cycloalkyl, 6-membered cycloalkyl, or 4-, 5- or 6-heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 substituents selected from RA;

or, W and R41 together with the carbon atom(s) to which they are each attached form 4-, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, wherein the heterocycloalkyl is optionally further substituted with 1, 2 or 3 substituents selected from RA;
5 or, R51 and R61, or R61 and R62 together with the carbon atom(s) to which they are each attached form 3-membered cycloalkyl, 4-membered cycloalkyl, 5-membered cycloalkyl, 4-, 5- or 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, or a double bond, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1, 2 or 3 RA
1 0 substituents;
Or, R61, R62 and R63 together with the carbon atom to which they are attached form 5-membered bicyclic bridged ring, 6-membered bicyclic bridged ring, 7-membered bicyclic bridged ring, 8-membered bicyclic bridged ring. 5-membered spiro ring, 6-membered spiro ring, 7-membered spiro ring, 8-membered spiro ring, 15 9-membered spiro ring, or 10-membered spiro ring, wherein the bridged ring and spiro ring are optionally further substituted with 1, 2 or 3 substituents selected from RA;
RA is selected from deuterium, F, Cl, amino, cyano, hydroxyl, C1_4 alkyl, halo C1-4 alkyl, deuterated CI _4 alkyl, C1-4 alkoxy, halo C1-4 alkoxy, deuterated 20 alkoxy, or hydroxy Cl_4alkyl.

6. The compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to any one of claims 1-4, characterised in that 25 Z is selected from NR' or 0;
W is selected from H, deuterium, methyl, ethyl, n-propyl or isopropyl;
R6,1 Ru R51 Ru A2-K ,R62 / \

R61 is selected from the following groups:

F >,------...7õ,---, F
I
H2N ' H2N F T.CF 3 ,i../'\ \¨ H2N
\N H2 H2N
V-- 'F
.J' H2N \ /
, =r"XIC/ H2N \ /C-'T H2 N

">0 F
F
''/(TY
-'\---"
H2 N ' ,----0 =-=---x----,,,,..-----, ' NH2 ,¨>--- H2N CF3 H2N H2 N H2N H2N F Fi21\
µ0.<

F1:1\IC2'r V---. .----, H2N ..---' 'OH )C\7 \
OH
H2N' 'OH

,k X ---,R62 z Or, R61 1S selected from .

7. The compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to claim 1, having a structure of formula (Ib):
-.,.
N" 1 .1. .Nõ R2 Ri..--'' R51 ,w2 0 7 X '-'=--- -R63 H2N \ R61 (Ib) is selected from halo CI _3 alkyl, -NHC(0)C1_4 alkyl, -NHC(0)C3-6 cycloalkyl, -NHC(0)C4-6 heterocycloalkyl, -NHC(0)NHCi_4 alkyl, or -NHC(0)0C1_4 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 substituents selected from deuterium, F, Cl, 5 amino, cyano, or hydroxyl;
R2 is selected from cyano, halo CI -3 alkyl or deuterated CI -3 alkyl;
R51 and R52 are each independently selected from II or deuterium;
R61 is independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, CI _6 alkyl, halo CI _6 alkyl, deuterated CI _6 alkyl, CI -6 alkoxy, halo CI -6 10 alkoxy, -C _6 alkyl-C3_6 cycloalkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, deuterated CI -6 alkoxy or hydroxy CI -6 alkyl;
R62 and R63 are each independently selected from halogen, amino, cyano, hydroxyl, CI -6 alkyl, halo CI -6 alkyl, deuterated CI -6 alkyl, CI -6 alkoxy, halo CI -6 15 alkoxy, -C _6 alkyl-C3-6 cycloalkyl, C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-3 heteroatoms selected from N, S and 0, deuterated CI 6 alkoxy, or hydroxy C1-6 alkyl;
Or, R61 and R62 together with the carbon atom(s) to which they are each attached form C3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl containing 1-20 heteroatoms selected from N, S and 0, or a double bond, wherein the cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 substituents selected from deuterium, F, Cl, amino, cyano, or hydroxyl.

8.
The compound, or the stereoisomer, deuterated compound, solvate, 25 prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to claim 7, characterised in that R1 is selected from halo C1-3 alkyl, -NHC(0)C1-4 alkyl, -NHC(0)C3-6 cycloalkyl, or -NHC(0)0C1-4 alkyl, wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally further substituted with 1-3 substituents selected 30 from deuterium, F, CI, amino, cyano, or hydroxyl;
R2 is selected from cyano or halo CI -3 alkyl;
R51 and R52 are each independently selected from H or deuterium;
R61 is independently selected from H, deuterium, halogen, amino, cyano, hydroxyl, CI -3 alkyl, or hydroxy C1_3 alkyl;

R62 and R63 are each independently selected from halogen, amino, cyano, hydroxyl, C1_3 alkyl, halo C1 -3 alkyl, deuterated C1 -3 alkyl, or hydroxy C1_3 alkyl;
or, R61 and R62 together with the carbon atom(s) to which they are each attached form C3 6 cycloalkyl or a double bond, wherein the cycloalkyl is 5 optionally further substituted with 1-3 substituents selected from deuterium, F, Cl, amino, cyano, or hydroxyl.

9. The compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof 10 according to claim 1, characterised in that the compound is selected from the following structures:
F N''''' 7 V."- F
'' F .,-/ cif,..1%1.., 1 ', F
F. ,....; N, ...LF II .1 N
I
./. Fy F .. -.7 , ,õ( .....y F
F ./ Nõ.1,...J.,F
1 ,./ ...---õ,.../... , 3 H"2:7<ry F CF

J
/4" F N'''. F N'. F Ni'l I Fy....." , I Nr Fy.k.õ...../ ..f..NxCoHF2 F
F
N. F F. ...'" r I
I F F 1 0....õ.KTAF3 1 ' F
^J, F '' ' g')''F
OH2N , H2N CF3 I.11-2N)Cri F F
'" F
F II----h) N F1 F. n A- IF I
N ..
F ../
NIJ F A ...J. , N, CHF2 --TF- u 'F rFifF
N
- 1-;r F H2N ' I
N' F NI '''' F 1,1' F
N.....'"- F
I I
F,õõ_.....k ' ..., ...")<--..,..
\
1-121, FH2N H2N
F N' `--- F , N =
N. ' F ' F
F I /= )., .N. J. F--11. ...-..,..,..N., al,. F., li 1 F
=
0--- F F 11,,,,,i.' =
N,, ,./..._ H2N l H2N ' F H2N
N '''` F /4, --- -),.,.c. F
N .."-D F F
F I ..., N.I..),F Fyi. /
NI,,....,F Fyit .../ N....x...1.,F F......12..,N.,...J.,õ
1 -i-F F
-F--12'C' I 0--2,, r /? : 0H2 -r, N .'" F
F.,õ_,,n,,N F ,..... I
11 :-; F
Nr F LF I , 1 F
I , F
F F
X=ACQL
H2N --F H2N `z 0:2;4)C, H2N _ N' DT, F N '-'),,r F N '-- F

F , ,It ..-- N,F Fyil ,., ..--- N F N F
F N - F I-1' I
It I F F F NF
F F
.., .--, ,.' H2N 'f '0,-,---2,:ri;, - 0-H-2----I-,0 F
"'----0-->"--3 N ."--- F t1111 N' "--'"-.D, N-.1-"k F
F A , N ,I.. F. - .,,-- ,N F.
, CHF2 .,T.,-11.. ,--- .N
F..CHF2 I ' N õ,,,LF
' ,,,,,, H2N ;IQ( H2N -N' F F N,' --) F N' 11.1.,r.,N F
F 11 ,--- N.1,,F F NI ,,,I,NT-1., Ky.!. , NI-LF F.i..11. -LF
F
I
F L!'' õ,-- .,-. ... ,-. F
1,--. ix, ,, -.., CF, F
H2N \ H2N. I H2N' I
:21, N''..I F N '-- F N'-'1. N"---1 F
F ,..-11. õ, ,N õ-k, F N. .1.. F ..11. .--- N., CHF2 F. 11 ..... N 1 Ti ,-,:r F T 1 , F
..., n X Ucr-F
1.---0---..1,--y F
n-2-N->c( H2N \

N'),, F N F N.-% F N --...
F
F..y.A., ...' N.,y),F F. (it õ..7.1,-....õck%L.,, F I õ,e N
1 "-F F .11, --'-.1:1 _,..] I 1 F F ,,,' ., F

H2N , H2N H2N1\ ,, 1 F
' 2__(µ
0 N" ,.. CN . 1...r._.. N'51.,õc, , --11-.N.k.-; ' .-.. NõxCoN '0j-11,1)--FF
...÷ cy ...õ..----,..rr-- N.
_..õ,:,1,0,,, H2N \ H2N2\--1r- H2N. \ 11 H2N"
N '1' -', F
O Nr'..), ,j,i_,..,...., 0 N---1 0 Ina r F. A.õ.....
---,c) r4 ...-- ---....CHF2 N, , I F k,,,0 H
.., \''Y :1-2N)\----''r H
-H21.-V H2N
F 1 ,r1 F .., yi4CHF2 F ...;12F
F
tir2NKX H2N
:1 ri 0 _Ira . , ". F 0 N. -, F
-.1N ,CF8 ,..-1.N ' -,--,,,,,,,,.CF3 H I H II o, ." ..,,,,,,,,,- ../ ..., H24 s 1 H2NTIC1C'F
O N -, 0 N '--0 1 ....- õT., --.0,N .., ,õ CHF2 , A ..,õ CHF2 ._,05,.,) wiy,i ' ..--- ,N1,1,F -,-Ø1.1 ' / 1 -..,,,HF2 I H N.
,,,,,,,Loõ, N' 0,-,:-.N N.--,42N \ 1 F Cn<''F
O ,111 p 0 N." 1 0 0 N.- i D
N.-. , F----).LN ..õ CN CN
H I H I H I I
-...1' E-1----;NiCF H?NiCr F OH'-'2N01 H'2'Nic-r-- 0 N.--F 9:-.1 I Nx-F1,F:Fõ.õN,,, CN A
NI ....- H I Fl F .:". cr"..A.-----, ,./ 0:2---'-'0H
H2N¨, V NH2 H2H OH
0 N''''' F
'-'0N1 N, 'F
H
H2N \ .

10. The compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to claim 1, characterised in that the compound is selected from the following structures:
N"- ,..
F
F N
F ....- Nõ F
, F
11..õ,õ( ..0,.õ.--..õ...,CF, H2N' FT '2/X-r-N "', F F
:õ... F1 IC. F N "'-. F
F 11,...,7-- Nõ

Fy...1 ...-= N, F
F

I I F\---xl...F
CF3 F An<

F H2I`f N I
õr H2ii 3 F
),-.
N' '-',1 F N '. , F N"" F
F -1 - N 1 Ry..k...,,.., N, 1,F F.,...,-J-1,-. .õNõ,õ-J...,F F 1:111. -.2-= N . ...CHF2 i , F F
I- ' iõX 'F I F
H2NY l'' I
NH-;T----T T-T' .--µ..
, N. = ., F ,,, N , F N----1 F N ', F

F 1 = 1 N I....rõ......1.0, =,F
F' -F FI2N- OXL`.'-' F (.\
¨ \NFI2 N .,. F N " F N' DT, F

F .--- R F ..F .I.", F F. ., =11, ...."
it:..J.L.õ F.,,,,,Aõ,' ,N,-1--,F
F
V H-2 '11 ' :i><.F
F H2N' \ -___ci i.
N"---- F 1µ.1-'kl F N"---), F N'''''', F
11 1 N 1. F. --It ...-- _i:1¨__ F Fy .....õj...1:x0 F -"="- F_., -;'' '--- Yi ....õ. F
I
F.., ..- Ç.

O''i:
H2N.' H2N.' H2N

Fy-11. ..."= " F ' .....- N F --- Nõ F

I F FF
H2N:F H2N :2,4XJ:7 N''--)- F N'), F N ..---- F
F õ...1,,../ ,N, õ.1.,'- , N"--""). ,,, F
F 'T F..,..,õ-,N-õ...õ)., -.7.' F -'".- '0' 'N' '')....õ F -'-'' ' '-X-''C \O 1 7 Flii H2N s Lei H2N
' ?-1'2N \-F. )1N' NC
S1 F N' %J 11"
)' N A CHF2 F. ..-., . N...õ..r.CHF2 F ....:: N .-I-F
'''' 'F
H2 v H2 r FI
0,.7....:,K--y-14 H2N 14 '---- H2N
N""'-). F 1,1' F F -._ N.' k-) F 14"'"--)Nc. F
y12,./.. IN,......,F F yl! ...-- N..1.1-,F
I F F
'1" I
F ...õ-- ,01T-21A,,,-...._.CF3 F
H2NA F 4 - . F H-2--NT-N .,. F N' '-'-'),,,.,..[ F N' .D.- .,,,,f N ,. F

F F F., )1. ../ ,N, ),,F F )1. .., ,N CHF2 F XD, I T 1 T "T I -1-- 7---_.
F
'N- --y- --(H tit i --- '11.---2?c( F-'0'-X'V
F
H2N H2N \
N"-',A.c.....õ....õ. N'-',- F N" ---. F
F ...-= N...x.-1,F F I
N--',), F
F F.
)1...õ--- ,...Ny-1.,F

µ H2N.

o 9 N.'. 1 0 NIC'' ' :

NK'), CN I
.tel.kõ, CN
I F
H 11 'a H I
-, .,..,õ ----0 N
H N -, 0,-.QH:NV-f-F ;Cr 1-12/e % II
H:II> 1-F
I-_ JO, 1 k,F,õ, ':-L111::OL.N F I N. _ I
H I , I ;c N.,-- ...,.µ,-. F
õ
..õ, OH
HA' µ I H2N1' 2XI ?r F N"'1, F-,(1-1../ NI, F --- I NI, CHF2 I , F
I-2N-> .) : F
';:isi'N'CL
I. NI ,, )% F oa i N
F
,N.ill f-.) ,T, ,,,. ,CF3 CF, N F
Am)iN,)NF
H I H I H''- r H:N"' 'Cci,ic F
o o N"F O HIM F o NI-", ,c, -111 7 1 4,,yCHF2 ..Ø1t ill 7 ,, CHF2 -..0,-n,tiN.:F ..0,-11.1CHF2 reCO' c`e I N ON;
, --, -F12Y N ..-' O
--,, ., F
:12;''-I(:
I-2k ' 1 4N-E FI2N N I
Ai 1 0 0 ,rfacx.00'1 N
I , 1 ---)OL r'r. 1 NH2 F ---)(11 H I
/ .----,...- --y---N'CI('F HA.' \ II H2WC( cr.10( NI' , 0 -F ---. ' ,N, -7 -.0N.NC 1,/ -."
-, ,,,,,,_,CF, K --I - -ON 0 N' " N '1 7(....11õN,1,,,,.. ,i, . . E = , , . , , õ; C N
..' .:12A-'-' '.H2NN I F F /
FI2A-Iv1 F F
0:2Ncy O,N N 0 N'' F (?' 1-,, F
CN ,L ikl.T.,N
0 Nõei,,,, '' I:N:11'T
H I
'0FicicOH (3-.- Cl'-')CV

11. A pharmaceutical composition, comprising the compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to any one of claims 1-10, and a 10 pharmaceutically acceptable carrier and/or excipient.

12. The pharmaceutical composition according to claim 11, comprising the compound, or the stereoisomer, deuterated compound, solvate, pharmaceutically acceptable salt or co-crystal thereof according to any one of 15 claims 1-10 in an amount selected from 1-1500 mg, and a carrier and/or excipient.

13. Use of the compound, or the stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof according to any one of claims 1-10, or the composition according to claim 11 or 20 12 in the preparation of a drug for treating an AAK1-mediated disease.

14. The use according to claim 13, characterised in that the AAK1-mediated disease is diabetic neuropathic pain or post-herpetic neuralgia.

15. The use according to claim 13, wherein, the amount of the compound, or the stereoisomer, deutcratcd compound, solvate, pharmaceutically acceptable salt or co-crystal thereof is 1-1500 mg.